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Two sample Mendelian Randomisation using an outcome from a multilevel model of disease progression. European journal of epidemiology Identifying factors that are causes of disease progression, especially in neurodegenerative diseases, is of considerable interest. Disease progression can be described as a trajectory of outcome over time-for example, a linear trajectory having both an intercept (severity at time zero) and a slope (rate of change). A technique for identifying causal relationships between one exposure and one outcome in observational data whilst avoiding bias due to confounding is two sample Mendelian Randomisation (2SMR). We consider a multivariate approach to 2SMR using a multilevel model for disease progression to estimate the causal effect an exposure has on the intercept and slope. We carry out a simulation study comparing a naïve univariate 2SMR approach to a multivariate 2SMR approach with one exposure that effects both the intercept and slope of an outcome that changes linearly with time since diagnosis. The simulation study results, across six different scenarios, for both approaches were similar with no evidence against a non-zero bias and appropriate coverage of the 95% confidence intervals (for intercept 93.4-96.2% and the slope 94.5-96.0%). The multivariate approach gives a better joint coverage of both the intercept and slope effects. We also apply our method to two Parkinson's cohorts to examine the effect body mass index has on disease progression. There was no strong evidence that BMI affects disease progression, however the confidence intervals for both intercept and slope were wide. 10.1007/s10654-023-01093-2
Genetic Evidence for Protective Effects of Angiotensin-Converting Enzyme Against Alzheimer Disease But Not Other Neurodegenerative Diseases in European Populations. Neurology. Genetics Background and Objectives:Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods:We performed genetic colocalization investigating an effect of cortical expression on AD risk in people of European ancestry. We further investigated whether any effect of expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results:There was genetic evidence supporting a protective effect of cortical expression on AD risk in people of European ancestry. Although higher cortical expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that expression affected risk of other neurodegenerative traits. Discussion:Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease. 10.1212/NXG.0000000000200014
Unique genetic architecture of CSF and brain metabolites pinpoints the novel targets for the traits of human wellness. Research square Brain metabolism perturbation can contribute to traits and diseases. We conducted the first large-scale CSF and brain genome-wide association studies, which identified 219 independent associations (59.8% novel) for 144 CSF metabolites and 36 independent associations (55.6% novel) for 34 brain metabolites. Most of the novel signals (97.7% and 70.0% in CSF and brain) were tissue specific. We also integrated MWAS-FUSION approaches with Mendelian Randomization and colocalization to identify causal metabolites for 27 brain and human wellness phenotypes and identified eight metabolites to be causal for eight traits (11 relationships). Low mannose level was causal to bipolar disorder and as dietary supplement it may provide therapeutic benefits. Low galactosylglycerol level was found causal to Parkinson's Disease (PD). Our study expanded the knowledge of MQTL in central nervous system, provided insights into human wellness, and successfully demonstrates the utility of combined statistical approaches to inform interventions. 10.21203/rs.3.rs-2923409/v1
Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study. Frontiers in immunology Background:There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it is currently unclear whether these associations reflect causal relationships. Objective:To elucidate the causal relationship between immune cells and neurodegenerative diseases, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and methods:The exposure and outcome GWAS data used in this study were obtained from an open-access database (https://gwas.mrcieu.ac.uk/), the study employed two-sample MR analysis to assess the causal relationship between 731 immune cell features and four neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). All immune cell data was obtained from Multiple MR methods were used to minimize bias and obtain reliable estimates of the causal relationship between the variables of interest and the outcomes. Instrumental variable selection criteria were restricted to ensure the accuracy and effectiveness of the causal relationship between species of immune cells and the risk of these neurodegenerative diseases. Results:The study identified potential causal relationships between various immune cells and different neurodegenerative diseases. Specifically, we found that 8 different types of immune cells have potential causal relationships with AD, 1 type of immune cells has potential causal relationships with PD, 6 different types of immune cells have potential causal relationships with ALS, and 6 different types of immune cells have potential causal relationships with MS. Conclusion:Our study, through genetic means, demonstrates close causal associations between the specific types of immune cells and AD, PD, ALS and MS, providing useful guidance for future clinical researches. 10.3389/fimmu.2024.1339649
The shared genetic landscape of blood cell traits and risk of neurological and psychiatric disorders. Cell genomics Phenotypic associations have been reported between blood cell traits (BCTs) and a range of neurological and psychiatric disorders (NPDs), but in most cases, it remains unclear whether these associations have a genetic basis and, if so, to what extent genetic correlations reflect causality. Here, we report genetic correlations and Mendelian randomization analyses between 11 NPDs and 29 BCTs, using genome-wide association study summary statistics. We found significant genetic correlations for four BCT-NPD pairs, all of which have prior evidence for a phenotypic correlation. We identified a previously unreported causal effect of increased platelet distribution width on susceptibility to Parkinson's disease. We identified multiple functional genes and regulatory elements for specific BCT-NPD pairs, some of which are targets of known drugs. These results enrich our understanding of the shared genetic landscape underlying BCTs and NPDs and provide a robust foundation for future work to improve prognosis and treatment of common NPDs. 10.1016/j.xgen.2022.100249
Joint Analysis of Genome-Wide Association Data Reveals No Genetic Correlations Between Low Back Pain and Neurodegenerative Diseases. Wu Pengfei,Du Bing,Wang Bing,Yin Rui,Lv Xin,Dai Yuliang,Zhang Wan,Xia Kun Frontiers in genetics We aimed to explore the genetic correlation and bidirectional causal relationships between low back pain (LBP) and three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Summary-level statistics were obtained from genome-wide association studies of LBP ( = 177,860), AD ( = 63,926), PD ( = 482,730), and ALS ( = 80,610). We implemented linkage disequilibrium score regression to calculate heritability estimates and genetic correlations. To investigate possible causal associations between LBP and three neurodegenerative diseases, we also conducted a bidirectional two-sample Mendelian randomization (MR) study. Inverse variance-weighted MR was employed as the primary method to generate overall estimates, whereas complementary approaches and sensitivity analyses were conducted to confirm the consistency and robustness of the findings. There was no evidence of genetic correlations between LBP and AD ( = -0.033, = 0.766). MR analyses did not support the causal effect of LBP on AD ( = 1.031; 95% CI, 0.924-1.150; = 0.590) or the effect of AD on LBP ( = 0.963; 95% CI, 0.923-1.006; = 0.090). Likewise, this study failed to identify genetic correlations between LBP and two other neurodegenerative diseases. MR results of the associations of LBP with PD and ALS, and the reverse associations, did not reach Bonferroni-corrected significance. The study did not support genetic correlations or causations between LBP and three common neurodegenerative diseases, AD, PD, and ALS in the European population. 10.3389/fgene.2021.744299
Polygenic risk of type 2 diabetes is associated with incident vascular dementia: a prospective cohort study. Brain communications Type 2 diabetes and dementia are associated, but it is unclear whether the two diseases have common genetic risk markers that could partly explain their association. It is also unclear whether the association between the two diseases is of a causal nature. Furthermore, few studies on diabetes and dementia have validated dementia end-points with high diagnostic precision. We tested associations between polygenic risk scores for type 2 diabetes, fasting glucose, fasting insulin and haemoglobin A as exposure variables and dementia as outcome variables in 29 139 adults (mean age 55) followed for 20-23 years. Dementia diagnoses were validated by physicians through data from medical records, neuroimaging and biomarkers in cerebrospinal fluid. The dementia end-points included all-cause dementia, mixed dementia, Alzheimer's disease and vascular dementia. We also tested causal associations between type 2 diabetes and dementia through two-sample Mendelian randomization analyses. Seven different polygenic risk scores including single-nucleotide polymorphisms with different significance thresholds for type 2 diabetes were tested. A polygenic risk score including 4891 single-nucleotide polymorphisms with a -value of <5e-04 showed the strongest association with different outcomes, including all-cause dementia (hazard ratio 1.11; Bonferroni corrected = 3.6e-03), mixed dementia (hazard ratio 1.18; Bonferroni corrected = 3.3e-04) and vascular dementia cases (hazard ratio 1.28; Bonferroni corrected = 9.6e-05). The associations were stronger for non-carriers of the Alzheimer's disease risk gene ε4. There was, however, no significant association between polygenic risk scores for type 2 diabetes and Alzheimer's disease. Furthermore, two-sample Mendelian randomization analyses could not confirm a causal link between genetic risk markers of type 2 diabetes and dementia outcomes. In conclusion, polygenic risk of type 2 diabetes is associated with an increased risk of dementia, in particular vascular dementia. The findings imply that certain people with type 2 diabetes may, due to their genetic background, be more prone to develop diabetes-associated dementia. This knowledge could in the future lead to targeted preventive strategies in clinical practice. 10.1093/braincomms/fcad054
The Dementias Platform UK (DPUK) Data Portal. European journal of epidemiology The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee. 10.1007/s10654-020-00633-4
A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. Lesnick Timothy G,Papapetropoulos Spiridon,Mash Deborah C,Ffrench-Mullen Jarlath,Shehadeh Lina,de Andrade Mariza,Henley John R,Rocca Walter A,Ahlskog J Eric,Maraganore Demetrius M PLoS genetics While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38)), survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48)), and PD age at onset (R(2) = 0.68, p = 1.68 x 10(-51)). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers. 10.1371/journal.pgen.0030098
omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases. American journal of human genetics Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (p < 2.95 × 10 and p > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community. 10.1016/j.ajhg.2023.12.006
Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Bandres-Ciga Sara,Noyce Alastair J,Hemani Gibran,Nicolas Aude,Calvo Andrea,Mora Gabriele, , ,Tienari Pentti J,Stone David J,Nalls Mike A,Singleton Andrew B,Chiò Adriano,Traynor Bryan J Annals of neurology OBJECTIVE:To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). METHODS:Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. RESULTS:We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. INTERPRETATION:Here, we have developed a public resource (https://lng-nia.shinyapps.io/mrshiny) which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481. 10.1002/ana.25431
Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system. Progress in neuro-psychopharmacology & biological psychiatry The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases. 10.1016/j.pnpbp.2023.110903
Does COVID-19 increase the risk of neuropsychiatric sequelae? Evidence from a mendelian randomization approach. World journal of psychiatry Observational studies based on electronic health records (EHR) report an increased risk of neurological/neuropsychiatric sequelae for patients who have had coronavirus disease 2019 (COVID-19). However, these studies may suffer from biases such as unmeasured confounding, residual reverse causality, or lack of precision in EHR-based diagnoses. To rule out these biases, we tested causal links between COVID-19 and different potential neurological/neuropsychiatric sequelae through a two-sample Mendelian randomization analysis of summary statistics from large Genome-Wide Association Scans of susceptibility to COVID-19 and different neurological and neuropsychiatric disorders, including major depression, anxiety, schizophrenia, stroke, Parkinson's and Alzheimer's diseases. We found robust evidence suggesting that COVID-19 - notably the hospitalized and most severe forms - carries an increased risk of neuropsychiatric sequelae, particularly Alzheimer's disease, and to a lesser extent anxiety disorder. In line with a large longitudinal EHR-based study, this evidence was stronger for more severe COVID-19 forms. These results call for a targeted screening strategy to tackle the post-COVID neuropsychiatric pandemic. 10.5498/wjp.v12.i3.536
Psoriasis and risk of central neurological disorders in European populations: A mendelian randomization analysis. Heliyon Background:People with psoriasis are at a higher risk for having central neurological problems, according to previous studies; however, it is unclear if there is a genetic link between the risk of developing psoriasis and developing central neurological disorders. In this study, the possible link between genetically predisposed psoriasis and the risk of common central nervous system disorders was comprehensively investigated. Methods:There was no overlap in the participant populations between the psoriasis and central neurological disorders genome-wide association studies, which provide the genetic resources. Inverse variance weighting, often used as Mendelian randomization (MR) analysis, is the main method. To guarantee the accuracy of our findings, a number of sensitivity studies were carried out. Results:MR analysis revealed that although psoriasis was reported to increase the risk of Parkinson's disease (OR = 4.42, 95%CI[-3.81~6.79], P = 0.58) and epilepsy (OR = 4.71, 95%CI[-2.20~5.30], P = 0.42) in this study, they did not reach statistical significance. At the same time, this study did not observe that psoriasis would increase the risk of multiple sclerosis (OR = 0.01, 95%CI [-12.61~3.83], P = 0.30) and migraine (OR = 0.99, 95%CI [0.94~1.05], P = 0.78), they also did not reach statistical significance. Under all sensitivity assessments, the results remained stable. Conclusions:Psoriasis does not appear to raise the risk of migraine, Parkinson's disease, multiple sclerosis, or epilepsy, according to our study. 10.1016/j.heliyon.2024.e24774
Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease. Vallerga Costanza L,Zhang Futao,Fowdar Javed,McRae Allan F,Qi Ting,Nabais Marta F,Zhang Qian,Kassam Irfahan,Henders Anjali K,Wallace Leanne,Montgomery Grant,Chuang Yu-Hsuan,Horvath Steve,Ritz Beate,Halliday Glenda,Hickie Ian,Kwok John B,Pearson John,Pitcher Toni,Kennedy Martin,Bentley Steven R,Silburn Peter A,Yang Jian,Wray Naomi R,Lewis Simon J G,Anderson Tim,Dalrymple-Alford John,Mellick George D,Visscher Peter M,Gratten Jacob Nature communications An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD. 10.1038/s41467-020-15065-7
Genetic architecture of brain age and its causal relations with brain and mental disorders. Molecular psychiatry The difference between chronological age and the apparent age of the brain estimated from brain imaging data-the brain age gap (BAG)-is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p < 5 × 10) implicating neurological, metabolic, and immunological pathways - among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson's disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p = 7.9 × 10) and bipolar disorder (p = 1.35 × 10) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG. 10.1038/s41380-023-02087-y
Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease. Kim Yun Joong,Jeon Junbeom,Shin Jaemoon,Kim Nan Young,Hong Jeong Hoon,Oh Jae-Min,Hong SangKyoon,Kim Yeo Jin,Kim Young-Eun,Kang Suk Yun,Ma Hyeo-Il,Lee Unjoo,Yoon Jeehee Movement disorders : official journal of the Movement Disorder Society BACKGROUND AND OBJECTIVES:Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. METHODS:Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS:In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION:Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD. © 2017 International Parkinson and Movement Disorder Society. 10.1002/mds.27019
Growth Differentiation Factor 15 Is Associated With Alzheimer's Disease Risk. Frontiers in genetics BACKGROUND:Previous observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS:Using summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated ( < 5 × 10) with GDF-15 were selected as instrumental variables ( = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR-Egger, leave-one-out analysis, and Cochran's -test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages. RESULTS:MR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04-1.24; = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 ( = 0.450). The causal effects of GDF-15 on PD ( = 0.597) or ALS ( = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses. CONCLUSION:We highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target. 10.3389/fgene.2021.700371
Identification of novel proteins associated with movement-related adverse antipsychotic effects by integrating GWAS data and human brain proteomes. Psychiatry research Genome-wide association studies (GWAS) have identified some variants for movement-related adverse antipsychotic effects (MAAE), while how these variants confer MAAE remains unclear. We used the probabilistic Mendelian randomization (PMR) method to identify candidate proteins for MAAE by integrating MAAE GWASs and protein quantitative trait loci (pQTL) data. An independent pQTL data from the Banner project and brain-derived eQTL data were used to perform confirmatory PMR. A total of 56 proteins were identified as candidate targets for MAAE after false discovery rates (FDR) correction, such as GRIN2B, ADRA1A, and PED4B. 12 genes were replicated in the confirmatory PMR, and 18 genes had consistent evidence at the transcript level. Furthermore, we investigated the associations between candidate proteins and the motor symptoms of Parkinson's disease (PD). There were 24, 38, and 10 candidate proteins that were significantly associated with PD, PD motor subtypes, and PD motor progression, respectively. Enrichment analysis identified 34 GO terms and 17 pathways that may be involved in MAAE, such as glutamatergic synapse, glutamate receptor complex, and GABAergic synapse. Our study identified multiple candidate genes and pathways that were associated with MAAE, providing new insights into the biological mechanism of MAAE and targets for further mechanistic and therapeutic studies. 10.1016/j.psychres.2022.114791
The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease. Bandres-Ciga Sara,Saez-Atienzar Sara,Bonet-Ponce Luis,Billingsley Kimberley,Vitale Dan,Blauwendraat Cornelis,Gibbs Jesse Raphael,Pihlstrøm Lasse,Gan-Or Ziv, ,Cookson Mark R,Nalls Mike A,Singleton Andrew B Movement disorders : official journal of the Movement Disorder Society BACKGROUND:PD is a complex polygenic disorder. In recent years, several genes from the endocytic membrane-trafficking pathway have been suggested to contribute to disease etiology. However, a systematic analysis of pathway-specific genetic risk factors is yet to be performed. OBJECTIVES:To comprehensively study the role of the endocytic membrane-trafficking pathway in the risk of PD. METHODS:Linkage disequilibrium score regression was used to estimate PD heritability explained by 252 genes involved in the endocytic membrane-trafficking pathway including genome-wide association studies data from 18,869 cases and 22,452 controls. We used pathway-specific single-nucleotide polymorphisms to construct a polygenic risk score reflecting the cumulative risk of common variants. To prioritize genes for follow-up functional studies, summary-data based Mendelian randomization analyses were applied to explore possible functional genomic associations with expression or methylation quantitative trait loci. RESULTS:The heritability estimate attributed to endocytic membrane-trafficking pathway was 3.58% (standard error = 1.17). Excluding previously nominated PD endocytic membrane-trafficking pathway genes, the missing heritability was 2.21% (standard error = 0.42). Random heritability simulations were estimated to be 1.44% (standard deviation = 0.54), indicating that the unbiased total heritability explained by the endocytic membrane-trafficking pathway was 2.14%. Polygenic risk score based on endocytic membrane-trafficking pathway showed a 1.25 times increase of PD risk per standard deviation of genetic risk. Finally, Mendelian randomization identified 11 endocytic membrane-trafficking pathway genes showing functional consequence associated to PD risk. CONCLUSIONS:We provide compelling genetic evidence that the endocytic membrane-trafficking pathway plays a relevant role in disease etiology. Further research on this pathway is warranted given that critical effort should be made to identify potential avenues within this biological process suitable for therapeutic interventions. © 2019 International Parkinson and Movement Disorder Society. 10.1002/mds.27614
omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases. medRxiv : the preprint server for health sciences Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer's Disease, highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use Summary-data-based Mendelian Randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer's disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson's disease, and 9 Progressive supranuclear palsy target genes passing multiple test corrections (p < 2.95×10 and p > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics - classifying 41 targets, 3 targets, and 115 targets (of these 69.8% are expressed in the disease relevant cell type from single nucleus experiments). Our class of genes provides a springboard for new opportunities in drug discovery, development and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as Riluzole in AD. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [https://nih-card-ndd-smr-home-syboky.streamlit.app/]. 10.1101/2023.04.06.23288266
Association Between Neurodegenerative Diseases and an Increased Risk of Epilepsy Based on Single Nucleotide Polymorphisms: A Mendelian Randomization Study. Molecular neurobiology Epilepsy is a common neurological disorder characterized by transient brain dysfunction, attributed to a multitude of factors. The purpose of this study is to explore whether neurodegenerative diseases, specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), have a causal effect on epilepsy. Mendelian randomization (MR) methods were used to analyze the causal association between neurodegenerative diseases (AD, PD, ALS, and MS) and epilepsy based on single nucleotide polymorphisms from genome-wide association studies, including inverse-variance weighted, weighted median, MR-Egger, and weighted mode methods. The reliability and stability of the MR analysis results were assessed by the MR-Egger intercept, MR-PRESSO, and heterogeneity tests. Forty-three SNPs were selected for the MR analysis of MS and epilepsy. The inverse-variance weighted method showed a significant causal association between MS and increased risk of epilepsy (odds ratio 1.046; 95% confidence interval 1.001-1.093; P = 0.043). However, AD (P = 0.986), PD (P = 0.894), and ALS (P = 0.533) were not causally associated with epilepsy. Sensitivity analysis showed that the results were robust. The MR study confirmed the causal relationship between genetically predicted MS and epilepsy but did not support the causal relationship between genetically predicted AD, PD, and ALS on epilepsy. 10.1007/s12035-024-03955-6
Genetically Predicted Milk Intake and Risk of Neurodegenerative Diseases. Zhang Zhizhong,Wang Mengmeng,Yuan Shuai,Larsson Susanna C,Liu Xinfeng Nutrients Milk intake has been associated with risk of neurodegenerative diseases in observational studies. Nevertheless, whether the association is causal remains unknown. We adopted Mendelian randomization design to evaluate the potential causal association between milk intake and common neurodegenerative diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Genetic associations for neurodegenerative diseases were obtained from the International Multiple Sclerosis Genetics Consortium ( = 80,094), FinnGen consortium ( = 176,899), AD GWAS ( = 63,926), Web-Based Study of Parkinson's Disease ( = 308,518), PDGene ( = 108,990), and ALS GWAS ( = 80,610). Lactase persistence variant rs4988235 (-13910 C > T) was used as the instrumental variable for milk intake. Genetically predicted higher milk intake was associated with a decreased risk of MS and AD and with an increased risk of PD. For each additional milk intake increasing allele, the odds ratios were 0.94 (95% confidence intervals [CI]: 0.91-0.97; = 1.51 × 10) for MS, 0.97 (0.94-0.99; = 0.019) for AD and 1.09 (95%CI: 1.06-1.12, = 9.30 × 10) for PD. Genetically predicted milk intake was not associated with ALS (odds ratio: 0.97, 95%CI: 0.94-1.01, = 0.135). Our results suggest that genetically predicted milk intake is associated with a decreased risk of MS and AD but with an increased risk of PD. Further investigations are needed to clarify the underlying mechanisms. 10.3390/nu13082893
The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES:To perform the largest PD genome-wide association study restricted to a single country. METHODS:We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS:We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS:Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. 10.1002/mds.27864
Transcriptomic analysis reveals associations of blood-based A-to-I editing with Parkinson's disease. Journal of neurology BACKGROUND:Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD). OBJECTIVE:We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD. METHODS:The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD. RESULTS:We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD. CONCLUSIONS:We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease. 10.1007/s00415-023-12053-x
Investigating Causality and Shared Genetic Architecture between Neurodegenerative Disorders and Inflammatory Bowel Disease. Aging and disease Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders. 10.14336/AD.2022.12209
Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics. Neurobiology of aging Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation. We next implemented a gene-centric pleiotropy analysis with a powerful method called PLACO and detected 280 pleiotropic associations (226 unique genes) with these diseases. Functional analyses demonstrated that these genes were enriched in the pancreas, liver, heart, blood, brain, and muscle tissues; and that 42 pleiotropic genes exhibited drug-gene interactions with 341 drugs. Using Mendelian randomization, we discovered that AD and PD can increase the risk of developing ALS, and that AD and ALS can also increase the risk of developing FTD, respectively. Overall, this study provides in-depth insights into shared genetic components and causal relationship among the 4 major neurodegenerative diseases, indicating genetic overlap and causality commonly drive their co-occurrence. It also has important implications on the etiology understanding, drug development and therapeutic targets for neurodegenerative diseases. 10.1016/j.neurobiolaging.2022.12.012
Assessing Causal Relationship Between Human Blood Metabolites and Five Neurodegenerative Diseases With GWAS Summary Statistics. Chen Haimiao,Qiao Jiahao,Wang Ting,Shao Zhonghe,Huang Shuiping,Zeng Ping Frontiers in neuroscience Neurodegenerative diseases (NDDs) are the leading cause of disability worldwide while their metabolic pathogenesis is unclear. Genome-wide association studies (GWASs) offer an unprecedented opportunity to untangle the relationship between metabolites and NDDs. By leveraging two-sample Mendelian randomization (MR) approaches and relying on GWASs summary statistics, we here explore the causal association between 486 metabolites and five NDDs including Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and multiple sclerosis (MS). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. We also performed linkage disequilibrium score regression (LDSC) and colocalization analyses to distinguish causal metabolite-NDD associations from genetic correlation and LD confounding of shared causal genetic variants. Finally, a metabolic pathway analysis was further conducted to identify potential metabolite pathways. We detected 164 metabolites which were suggestively associated with the risk of NDDs. Particularly, 2-methoxyacetaminophen sulfate substantially affected ALS (OR = 0.971, 95%CIs: 0.961 ∼ 0.982, FDR = 1.04E-4) and FTD (OR = 0.924, 95%CIs: 0.885 ∼ 0.964, FDR = 0.048), and X-11529 (OR = 1.604, 95%CIs: 1.250 ∼ 2.059, FDR = 0.048) and X-13429 (OR = 2.284, 95%CIs: 1.457 ∼ 3.581, FDR = 0.048) significantly impacted FTD. These associations were further confirmed by the weighted median and maximum likelihood methods, with MR-PRESSO and the MR-Egger regression removing the possibility of pleiotropy. We also observed that ALS or FTD can alter the metabolite levels, including ALS and FTD on 2-methoxyacetaminophen sulfate. The LDSC and colocalization analyses showed that none of the identified associations could be driven by genetic correlation or confounding by LD with common causal loci. Multiple metabolic pathways were found to be involved in NDDs, such as "urea cycle" ( = 0.036), "arginine biosynthesis" ( = 0.004) on AD and "phenylalanine, tyrosine and tryptophan biosynthesis" ( = 0.046) on ALS. our study reveals robust bidirectional causal associations between servaral metabolites and neurodegenerative diseases, and provides a novel insight into metabolic mechanism for pathogenesis and therapeutic strategies of these diseases. 10.3389/fnins.2021.680104
Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. Acta neuropathologica communications Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta, total tau, and phosphorylated tau as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta levels (effect = - 0.5, p = 9.2 × 10). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta (R = 2.29%; p = 2.5 × 10). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta levels (p = 7.3 × 10). Two-sample Mendelian Randomization revealed that CSF amyloid beta plays a role in Parkinson's disease (p = 1.4 × 10) and age at onset (p = 7.6 × 10), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta (p = 3.8 × 10), higher mean cortical binding potentials (p = 5.8 × 10), and higher Braak amyloid beta score (p = 4.4 × 10). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta, and APOE. 10.1186/s40478-020-01072-8
Menopause accelerates biological aging. Levine Morgan E,Lu Ake T,Chen Brian H,Hernandez Dena G,Singleton Andrew B,Ferrucci Luigi,Bandinelli Stefania,Salfati Elias,Manson JoAnn E,Quach Austin,Kusters Cynthia D J,Kuh Diana,Wong Andrew,Teschendorff Andrew E,Widschwendter Martin,Ritz Beate R,Absher Devin,Assimes Themistocles L,Horvath Steve Proceedings of the National Academy of Sciences of the United States of America Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further. 10.1073/pnas.1604558113
Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. BMJ (Clinical research ed.) 10.1136/bmj.j3170
Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study. PLoS medicine BACKGROUND:Both positive and negative associations between higher body mass index (BMI) and Parkinson disease (PD) have been reported in observational studies, but it has been difficult to establish causality because of the possibility of residual confounding or reverse causation. To our knowledge, Mendelian randomisation (MR)-the use of genetic instrumental variables (IVs) to explore causal effects-has not previously been used to test the effect of BMI on PD. METHODS AND FINDINGS:Two-sample MR was undertaken using genome-wide association (GWA) study data. The associations between the genetic instruments and BMI were obtained from the GIANT consortium and consisted of the per-allele difference in mean BMI for 77 independent variants that reached genome-wide significance. The per-allele difference in log-odds of PD for each of these variants was estimated from a recent meta-analysis, which included 13,708 cases of PD and 95,282 controls. The inverse-variance weighted method was used to estimate a pooled odds ratio (OR) for the effect of a 5-kg/m2 higher BMI on PD. Evidence of directional pleiotropy averaged across all variants was sought using MR-Egger regression. Frailty simulations were used to assess whether causal associations were affected by mortality selection. A combined genetic IV expected to confer a lifetime exposure of 5-kg/m2 higher BMI was associated with a lower risk of PD (OR 0.82, 95% CI 0.69-0.98). MR-Egger regression gave similar results, suggesting that directional pleiotropy was unlikely to be biasing the result (intercept 0.002; p = 0.654). However, the apparent protective influence of higher BMI could be at least partially induced by survival bias in the PD GWA study, as demonstrated by frailty simulations. Other important limitations of this application of MR include the inability to analyse non-linear associations, to undertake subgroup analyses, and to gain mechanistic insights. CONCLUSIONS:In this large study using two-sample MR, we found that variants known to influence BMI had effects on PD in a manner consistent with higher BMI leading to lower risk of PD. The mechanism underlying this apparent protective effect warrants further study. 10.1371/journal.pmed.1002314
Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis. Experimental dermatology Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level. 10.1111/exd.14984
Thirty novel sequence variants impacting human intracranial volume. Brain communications Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume ( = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including and that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder. 10.1093/braincomms/fcac271
The effect of onset age on the clinical features of Parkinson's disease. Wickremaratchi M M,Ben-Shlomo Y,Morris H R European journal of neurology Many clinicians view age at onset as an important determinant of clinical phenotype in Parkinson's disease (PD) and this has been reinforced by the identification of Mendelian genes that account for some cases of younger onset PD. A systematic review of OVID Medline for articles relevant to the relationship between clinical features and age at onset in PD published in English between 1950-2007 was performed. There are very few prospective community based studies which focus on the relationship between age at onset and the features of PD and a variety of case definitions are used in the literature. Most studies of young onset PD are based on specialist clinic referral series. The available evidence suggests that PD patients with a younger age at onset have: (i) a slower disease progression, (ii) an increased rate of dystonia at onset and during treatment, (iii) a lower rate of dementia and (iv) an increased rate of dyskinesias in response to L-DOPA treatment. The majority of the available studies do not report patient genotype data, but it is probably that the clinical heterogeneity of PD will be further refined with detailed clinico-genetic studies. 10.1111/j.1468-1331.2008.02514.x
Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy. Computational and structural biotechnology journal Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer's disease (AD), Parkinson's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (  = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results. 10.1016/j.csbj.2022.08.006
Discovering genetic mechanisms underlying the co-occurrence of Parkinson's disease and non-motor traits. NPJ Parkinson's disease Understanding the biological mechanisms that underlie the non-motor symptoms of Parkinson's disease (PD) requires comprehensive frameworks that unravel the complex interplay of genetic risk factors. Here, we used a disease-agnostic brain cortex gene regulatory network integrated with Mendelian Randomization analyses that identified 19 genes whose changes in expression were causally linked to PD. We further used the network to identify genes that are regulated by PD-associated genome-wide association study (GWAS) SNPs. Extended protein interaction networks derived from PD-risk genes and PD-associated SNPs identified convergent impacts on biological pathways and phenotypes, connecting PD with established co-occurring traits, including non-motor symptoms. These findings hold promise for therapeutic development. In conclusion, while distinct sets of genes likely influence PD risk and outcomes, the existence of genes in common and intersecting pathways associated with other traits suggests that they may contribute to both increased PD risk and symptom heterogeneity observed in people with Parkinson's. 10.1038/s41531-024-00638-w
Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes. Aging Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (, , , , ) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD. 10.18632/aging.205444
Genome-wide QTL mapping across three tissues highlights several Alzheimer's and Parkinson's disease loci potentially acting via DNA methylation. medRxiv : the preprint server for health sciences DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-wide single nucleotide polymorphism (SNP; ~5.5M sites) and DNAm (~850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10) SNP-CpG associations in each tissue. Combining these meQTL GWAS results with recent AD/PD GWAS summary statistics by MR strongly suggests that the previously described associations between , , and and AD may be founded on differential DNAm in or near these genes. In addition, there is strong, albeit less unequivocal, support for causal links between DNAm at in AD as well as at in AD and PD. Our study adds valuable insights on AD/PD pathogenesis by combining two high-resolution "omics" domains, and the meQTL data shared along with this publication will allow like-minded analyses in other diseases. 10.1101/2023.12.22.23300365
Disease-modifying vs symptomatic treatments: Splitting over lumping. Handbook of clinical neurology Clinical trials of putative disease-modifying therapies in neurodegeneration have obeyed the century-old principle of convergence, or lumping, whereby any feature of a clinicopathologic disease entity is considered relevant to most of those affected. While this convergent approach has resulted in important successes in trials of symptomatic therapies, largely aimed at correcting common neurotransmitter deficiencies (e.g., cholinergic deficiency in Alzheimer's disease or dopaminergic deficiency in Parkinson's disease), it has been consistently futile in trials of neuroprotective or disease-modifying interventions. As individuals affected by the same neurodegenerative disorder do not share the same biological drivers, splitting such disease into small molecular/biological subtypes, to match people to therapies most likely to benefit them, is vital in the pursuit of disease modification. We here discuss three paths toward the splitting needed for future successes in precision medicine: (1) encourage the development of aging cohorts agnostic to phenotype in order to enact a biology-to-phenotype direction of biomarker development and validate divergence biomarkers (present in some, absent in most); (2) demand bioassay-based recruitment of subjects into disease-modifying trials of putative neuroprotective interventions in order to match the right therapies to the right recipients; and (3) evaluate promising epidemiologic leads of presumed pathogenetic potential using Mendelian randomization studies before designing the corresponding clinical trials. The reconfiguration of disease-modifying efforts for patients with neurodegenerative disorders will require a paradigm shift from lumping to splitting and from proteinopathy to proteinopenia. 10.1016/B978-0-323-85555-6.00020-5
Letter to the editor-Association between depression and risk of Parkinson's disease in South Korean adults. Peng Haoxin,Lin Jinsheng,Guan Wenhui Journal of affective disorders 10.1016/j.jad.2021.09.006
Unbiased metabolome screen links serum urate to risk of Alzheimer's disease. Neurobiology of aging Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabolite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions. 10.1016/j.neurobiolaging.2022.09.004
Analysis of the Relationship Between Parkinson's Disease and Diabetic Retinopathy Based on Bioinformatics Methods. Molecular neurobiology The objective of the study was to explore the relationship and potential mechanism between Parkinson's disease (PD) and diabetic retinopathy (DR) using bioinformatics methods. We first examined the causal relationship between PD and DR by Mendelian randomization (MR) analysis. The datasets of PD and DR patients from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs). Then, we performed the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and immune infiltration analysis. We also constructed a protein-protein interaction network and receiver operating characteristic (ROC) curve. Finally, an online website was used for drug prediction. The MR analysis demonstrated a causal relationship between DR and PD (odds ratio [OR] = 0.86; 95% confidence interval [CI] 0.79-0.93; p = 3.24E - 04), in which DR acted as a protective factor against PD. There were 81 DEGs identified from the PD and DR datasets, of which 29 genes had protein interaction relationships, and enrichment analysis showed that these genes were mainly related to immune pathways. As indicated by immune cell infiltration analysis, the expression of immune cells between PD and the control group was significantly different. ROC curve results showed five genes had diagnostic value, and several potential chemical compounds were predicted to target the genes. Our findings demonstrate a reduced risk of PD in patients with DR. We also found that PD and DR are closely related in terms of inflammation, which provides clues for further exploring the common mechanisms and interaction of these two diseases. 10.1007/s12035-024-03982-3
Review of mendelian randomization studies on age at natural menopause. Frontiers in endocrinology Menopause marks the end of the reproductive phase of life. Based on epidemiological studies, abnormal age at natural menopause (ANM) is thought to contribute to a number of adverse outcomes, such as osteoporosis, cardiovascular disease, and cancer. However, the causality of these associations remains unclear. A powerful epidemiological method known as Mendelian randomization (MR) can be used to clarify the causality between ANM and other diseases or traits. The present review describes MR studies that included ANM as an exposure, outcome and mediator. The findings of MR analyses on ANM have revealed that higher body mass index, poor educational level, early age at menarche, early age at first live birth, early age at first sexual intercourse, and autoimmune thyroid disease appear to be involved in early ANM etiology. The etiology of late ANM appears to be influenced by higher free thyroxine 4 and methylene tetrahydrofolate reductase gene mutations. Furthermore, early ANM has been found to be causally associated with an increased risk of osteoporosis, fracture, type 2 diabetes mellitus, glycosylated hemoglobin, and the homeostasis model of insulin resistance level. In addition, late ANM has been found to be causally associated with an increased systolic blood pressure, higher risk of breast cancer, endometrial cancer, endometrioid ovarian carcinoma, lung cancer, longevity, airflow obstruction, and lower risk of Parkinson's disease. ANM is also a mediator for breast cancer caused by birth weight and childhood body size. However, due to the different instrumental variables used, some results of studies are inconsistent. Future studies with more valid genetic variants are needed for traits with discrepancies between MRs or between MR and other types of epidemiological studies. 10.3389/fendo.2023.1234324
Assessing causal relationship between circulating cytokines and age-related neurodegenerative diseases: a bidirectional two-sample Mendelian randomization analysis. Scientific reports Numerous studies have reported that circulating cytokines (CCs) are linked to age-related neurodegenerative diseases (ANDDs); however, there is a lack of systematic investigation for the causal association. A two-sample bidirectional Mendelian Randomisation (MR) method was utilized to evaluate the causal effect. We applied genetic variants correlated with concentrations of CCs from a genome-wide association study meta-analysis (n = 8293) as instrumental variables. Summary data of three major ANDDs [Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS)] were identified from the IEU OpenGWAS platform (n = 627, 266). Inverse-variance weighted method is the main approach to analyse causal effect, and MR results are verified by several sensitivity and pleiotropy analyses. In directional MR, it suggested that several CCs were nominally correlated with the risk of ANDDs, with a causal odds ratio (OR) of Interleukin (IL)-5 of 0.909 for AD; OR of IL-2 of 1.169 for PD; and OR of Beta nerve growth factor of 1.142 for ALS). In reverse MR, there were some suggestively causal effects of ANDDs on CCs (AD on increased Basic fibroblast growth factor and IL-12 and decreased Stem cell growth factor beta; PD on decreased Monokine induced by interferon-gamma; ALS on decreased Basic fibroblast growth factor and IL-17). The findings were stable across sensitivity and pleiotropy analyses. However, after Bonferroni correction, there is no statistically significant association between CCs and ANDDs. Through the genetic epidemiological approach, our study assessed the role and presented possible causal associations between CCs and ANDDs. Further studies are warranted to verify the causal associations. 10.1038/s41598-023-39520-9
Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study. Annals of translational medicine Background:Extensive observational studies have suggested an association between serum sex-hormone binding globulin (SHBG) and Alzheimer's disease (AD); however, causality remains unclear. Furthermore, the effects on other neurodegenerative diseases have been poorly investigated. We aimed to explore the causal effects of genetically predicted SHBG serum levels on common neurodegenerative diseases. Methods:A two-sample Mendelian randomization (MR) approach was used. Genetic variants of SHBG levels in the serum, detected using the chemiluminescent two-step sandwich immunoassay method, were identified from a genome-wide association meta-analysis from the UK Biobank (N=363,228). Summary-level data for AD, and other common neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were adopted from the corresponding large genome-wide association studies of individuals of European ancestry, which were either clinically or autopsy-diagnosed. Causal estimates were calculated using the inverse-variance weighted (IVW) method and several sensitivity methods (MR-Egger, weighted median, and weighted mode). Egger intercept, MR-PRESSO, and leave-one-out analyses were used to identify potential violations. Results:Genetically determined serum SHBG levels [odds ratio (OR) =1.113, 95% CI: 1.019-1.215, P=0.017] were associated with an increased risk of ALS. This causal effect was confirmed using sensitivity analyses, including the MR-Egger (OR =1.229, 95% CI: 1.049-1.441, P=0.012), weighted median (OR =1.231, 95% CI: 1.077-1.406, P=0.002), and weighted mode (OR =1.235, 95% CI: 1.067-1.431, P=0.005) methods. No notable heterogeneity or directional pleiotropy was observed. However, leave-one-out analysis showed that rs9892297 drove the observed effects. There was no evidence that genetically predicted serum SHBG levels affect other neurodegenerative diseases, including AD, PD, MS, DLB, and FTD (all P>0.05). Conclusions:This MR analysis found that genetically determined serum SHBG was associated with an increased risk of ALS rather than AD, which is inconsistent with previous observational studies. This novel finding highlights the potential of SHBG in peripheral serum for ALS prevention. Further research into the effects of SHBG on other neurodegenerative diseases is required, especially because of the increased utilization of hormone therapy. 10.21037/atm-22-1156
Assessment of relationships between bullous pemphigoid and neurological diseases: A bidirectional two-sample Mendelian randomization study. Experimental dermatology Bullous pemphigoid (BP) is the most prevalent autoimmune vesiculobullous skin illness that tends to affect the elderly. Growing evidence has hinted a correlation between BP and neurological diseases. However, existing observational studies contained inconsistent results, and the causality and direction of their relationship remain poorly understood. To assess the causal relationship between BP and neurological disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and stroke. A bidirectional two-sample Mendelian randomization (MR) adopted independent top genetic variants as instruments from the largest accessible genome-wide association studies (GWASs), with BP (n = 218 348), PD (n = 482 730), AD (n = 63 926), stroke (n = 446 696), and MS (n = 115 803). Inverse variance weighted (IVW), MR-Egger, weighted mode methods, weighted median, and simple mode were performed to explore the causal association. Multiple sensitivity analyses, MR-Pleiotropy Residual Sum and Outlier (PRESSO) was used to evaluate horizontal pleiotropy and remove outliers. With close-to-zero effect estimates, no causal impact of BP on the risk of the four neurological diseases was discovered. However, we found that MS was positively correlated with higher odds of BP (OR = 1.220, 95% CI: 1.058-1.408, p = 0.006), while no causal associations were observed between PD (OR = 0.821, 95% CI: 0.616-1.093, p = 0.176), AD (OR = 1.066, 95% CI: 0.873-1.358, p = 0.603), stroke (OR = 0.911, 95% CI: 0.485-1.713, p = 0.773) and odds of BP. In summary, no causal impact of BP on the risk of PD, AD, MS and stroke was detected in our MR analysis. However, reverse MR analysis identified that only MS was positively correlated with higher odds of BP, but not PD, AD and stroke. 10.1111/exd.14869
Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis. Frontiers in aging neuroscience It has been previously postulated that blood neurotransmitters might affect risks of neurodegenerative diseases. Here, a Mendelian Randomization (MR) study was conducted to explore whether genetically predicted concentrations of glycine, glutamate and serotonin were associated with risks of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). From three genome-wide association studies of European ancestry, single nucleotide polymorphisms strongly associated with glycine, glutamate and serotonin were selected as genetic instrumental variables. Corresponding summary statistics were also obtained from the latest genome-wide association meta-analyses of AD, PD and ALS. The inverse-variance weighted MR and multiple sensitivity analyses were performed to evaluate causal effects of genetically predicted levels of neurotransmitters on risks of neurodegenerative diseases. The statistical significance threshold was set at < 0.0056 using the Bonferroni-correction, while 0.0056 < < 0.05 was considered suggestive evidence for a causal association. There was a causal association of elevated blood glutamate levels with higher AD risks. The odds ratio (OR) of AD was 1.311 [95% confidence interval (CI), 1.087-1.580; = 0.004] per one standard deviation increase in genetically predicted glutamate concentrations. There was suggestive evidence in support of a protective effect of blood serotonin on AD (OR = 0.607; 95% CI, 0.396-0.932; = 0.022). Genetically predicted glycine levels were not associated with the risk of AD (OR = 1.145; 95% CI, 0.939-1.396; = 0.180). Besides, MR analyses indicated no causal roles of three blood neurotransmitters in PD or ALS. In conclusion, the MR study provided evidence supporting the association of elevated blood glutamate levels with higher AD risks and the association of increased blood serotonin levels with lower AD risks. Triangulating evidence across further study designs is still warranted to elucidate the role of blood neurotransmitters in risks of neurodegenerative diseases. 10.3389/fnagi.2022.938408
Causal Association Between Sepsis and Neurodegenerative Diseases: A Bidirectional Two-Sample Mendelian Randomization Study. Journal of Alzheimer's disease : JAD BACKGROUND:Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear. OBJECTIVE:Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis. METHODS:Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane's Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability. RESULTS:The results of IVW indicated that sepsis significantly increased the risk of Alzheimer's disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy. CONCLUSIONS:The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis. 10.3233/JAD-230954
Sleep/wake cycle alterations as a cause of neurodegenerative diseases: A Mendelian randomization study. Cullell Natalia,Cárcel-Márquez Jara,Gallego-Fábrega Cristina,Muiño Elena,Llucià-Carol Laia,Lledós Miquel,Amaut Karol Enrique Uscamaita,Krupinski Jerzy,Fernández-Cadenas Israel Neurobiology of aging Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10 and 95%CI:-7.28 to -4.44, p = 5.87×10, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS. 10.1016/j.neurobiolaging.2021.05.008
Genetic Insights into the Risk of Metabolic Syndrome and Its Components on Dementia: A Mendelian Randomization. Journal of Alzheimer's disease : JAD BACKGROUND:The role of metabolic syndrome (MetS) on dementia is disputed. OBJECTIVE:We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. METHODS:The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the robustness of the results. RESULTS:Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p > 0.05). In addition, no significant association between MetS and its components and Alzheimer's disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson's disease (all p > 0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95% CI: 0.72-0.92, p = 0.0010). CONCLUSIONS:From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types. 10.3233/JAD-230623
Body Mass Index, Abdominal Adiposity, and Incidence of Parkinson Disease in French Women From the E3N Cohort Study. Neurology BACKGROUND AND OBJECTIVES:Previous studies on the relationship between body mass index (BMI) and Parkinson disease (PD) provided inconsistent results, likely due to reverse causation explained by weight loss during the prodromal phase. We examined the association of BMI and abdominal adiposity with PD incidence using lagged analyses to address the potential for reverse causation and compared BMI trajectories in patients before diagnosis and matched controls. METHODS:We used data from the E3N cohort study of French women with a 29-year follow-up (1990-2018). BMI (kg/m) was computed based on self-reported weight and height up to 11 times; up to 6 waist circumference (WC) and hip circumference measures were available. PD diagnoses were validated based on medical records and drug claim databases. Multivariable time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs according to BMI categories (underweight <18.5 kg/m; normal = [18.5-25.0[ kg/m; overweight = [25.0-30.0[ kg/m; obese ≥30.0 kg/m). Exposures were lagged by 5 years in main analyses; we used longer lags (10 and 20 years) in sensitivity analyses. We examined trajectories of BMI categories within a nested case-control study using multivariable generalized estimating equations multinomial logistic models. RESULTS:Of 96,702 women (baseline age = 40-65 years), 1,164 developed PD. PD incidence was lower (HR = 0.76, 95% CI = 0.59-0.98, = 0.032) among women with obesity compared with those with normal BMI. There was a similar association in analyses using longer lag times (20 years, 598 cases, HR = 0.52, 95% CI = 0.30-0.88, = 0.016). A similar pattern was seen for WC and waist-height ratio but not waist-hip ratio. Trajectories of BMI categories (1,196 patients and 23,876 controls) showed that obesity was less frequent in patients with PD before diagnosis than in controls, with a statistically significant difference 29 years before. In addition, the frequency of obesity decreased 5-10 years before diagnosis in patients. DISCUSSION:In this large cohort of women with a long follow-up, obesity was associated with a lower hazard of PD, even when measured 20 years before diagnosis, in agreement with Mendelian randomization studies. Our analyses underscore the importance of lagged analyses to account for reverse causation. These findings warrant further investigations to understand the mechanisms underlying this inverse association. 10.1212/WNL.0000000000201468
Genetic Liability to Sedentary Behavior in Relation to Stroke, Its Subtypes and Neurodegenerative Diseases: A Mendelian Randomization Study. Yang Fangkun,Chen Songzan,Qu Zihao,Wang Kai,Xie Xiaojie,Cui Hanbin Frontiers in aging neuroscience To investigate the causal association of domain-specific sedentary behaviors with cerebrovascular diseases and neurodegenerative diseases, and the potential mediators among these associations. Genetic instruments were identified for television watching, computer use and driving behavior from a genome-wide association study including 408,815 subjects. Mendelian randomization (MR) analysis was used to estimate the causal effect of sedentary behaviors on the cerebrovascular diseases and neurodegenerative diseases. Multivariable MR analysis was applied to adjust potential confounding factors, and mediation analysis was conducted to explore potential mediators. Genetically predisposition to 1.5 h/day increase in leisure time watching television was associated with increased risk of all-cause stroke [odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15-1.52, -value for MR-Egger method ( ) = 0.11, = 37%, Cochrane's Q = 212, -value for Cochran Q test ( ) < 0.001], and ischemic stroke (OR = 1.28, 95%CI = 1.10-1.49, = 0.04, = 35%, Cochrane's Q = 206, = 0.002). Interestingly, television watching may decrease the risk of Parkinson's disease (OR = 0.65, 95%CI = 0.50-0.84, = 0.47, = 19%, Cochrane's Q = 157, = 0.04). Television watching was a detrimental factor of cognitive performance (estimate = -0.46, 95%CI = -0.55 - -0.37, = 0.001, = 85%, Cochrane's Q = 862, < 0.001). Sensitivity analyses using leave out method and MR-PRESSO method suggested weak evidence of pleiotropy. We provided genetic evidence for the causal association of television watching with increased risk of all-cause stroke and ischemic stroke, decreased risk of Parkinson's disease, and worse cognitive performance. The results should be interpreted with caution considering the pleiotropy. 10.3389/fnagi.2021.757388
The causal role of circulating amino acids on neurodegenerative disorders: A two-sample Mendelian randomization study. Journal of neurochemistry Potential associations between the risk of neurodegenerative diseases and circulating levels of amino acids have been implied in both experimental research and observational studies. However, because of the confounding and reverse causality, the findings could be biased. We aimed to determine whether circulating amino acid levels have potential effects on the risk of neurodegenerative diseases through a more robust analysis. So, we performed a total of two MR analyses, a discovery two-sample MR analysis, and a replication test, using summary-level genome-wide association study (GWAS) data, both with circulating levels of amino acids as exposure and risk of neurodegenerative diseases as an outcome. The potential causalities between nine amino acids (Glutamine [Glu], Leucine [Leu], Isoleucine [Ile], Phenylalanine [Phe], Valine [Val], Alanine [Ala], Tyrosine [Tyr], Histidine [His], and Glycine [Gly]) and six neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], Multiple sclerosis [MS], Frontotemporal dementia [FTD], Lewy body dementia [DLB], Amyotrophic lateral sclerosis [ALS]) were explored in this study. According to the discovery MR analysis, 1 SD. increase in circulating levels of Gln was genetically determined to result in a 13% lower risk of AD (IVW OR [95% CI] = 0.872 [0.822, 0.926]; FDR = 7.46 × 10 ) while PD risk was decreased to 63% per SD. increase of circulating Leu levels (IVW OR [95% CI] = 0.628 [0.467, 0.843]; FDR = 0.021). Results from the replication test provide further evidence of the potential association between circulating Gln levels and AD risk (IVW OR [95% CI] = 0.094 [0.028, 0.311]; FDR = 9.98 × 10 ). Meanwhile, sensitivity analysis demonstrated that the significant relationships revealed by our two-sample MR outcomes were reliable. Our analyses provided robust evidence of causal associations between circulating levels of Gln and AD risk as well as circulating Leu levels and risk of PD. However, the underlying mechanisms remain to be further investigated. 10.1111/jnc.15937
Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. Prins Bram P,Abbasi Ali,Wong Anson,Vaez Ahmad,Nolte Ilja,Franceschini Nora,Stuart Philip E,Guterriez Achury Javier,Mistry Vanisha,Bradfield Jonathan P,Valdes Ana M,Bras Jose,Shatunov Aleksey, , , , , , , , , , , , , , ,Lu Chen,Han Buhm,Raychaudhuri Soumya,Bevan Steve,Mayes Maureen D,Tsoi Lam C,Evangelou Evangelos,Nair Rajan P,Grant Struan F A,Polychronakos Constantin,Radstake Timothy R D,van Heel David A,Dunstan Melanie L,Wood Nicholas W,Al-Chalabi Ammar,Dehghan Abbas,Hakonarson Hakon,Markus Hugh S,Elder James T,Knight Jo,Arking Dan E,Spector Timothy D,Koeleman Bobby P C,van Duijn Cornelia M,Martin Javier,Morris Andrew P,Weersma Rinse K,Wijmenga Cisca,Munroe Patricia B,Perry John R B,Pouget Jennie G,Jamshidi Yalda,Snieder Harold,Alizadeh Behrooz Z PLoS medicine BACKGROUND:C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS:We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS:Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes. 10.1371/journal.pmed.1001976
Causal relationship between gut microflora and dementia: a Mendelian randomization study. Frontiers in microbiology Background:Numerous pertinent investigations have demonstrated a correlation between gut microflora (GM) and the occurrence of dementia. However, a causal connection between GM and dementia and its subtypes has not yet been clarified. Objective:To explore the causal association between GM and dementia, including its subtypes, a two-sample Mendelian randomization (TSMR) analysis was used. Methods:Our data comes from the Genome-Wide Association Study (GWAS). The principal approach employed for the Mendelian randomization study was the inverse-variance weighted method, supplemented by four methods: MR-Egger, weighted median, simple mode, and weighted mode. This was followed by Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out as sensitivity analysis validation. Results:Twenty-one GMs associated with any dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, Parkinson's disease, and dementia under other disease classifications were derived from the analysis, and 21 passed sensitivity tests. Conclusion:We confirmed the causal relationship between GM and dementia and its subtypes, derived specific flora associated with increased or decreased risk of dementia, and provided new ideas for preventive, diagnostic, and therapeutic interventions for dementia mediated by gut microbiota. 10.3389/fmicb.2023.1306048
Appendectomy and the risk of neurodegenerative diseases: A two-sample Mendelian randomization study. Asian journal of surgery 10.1016/j.asjsur.2023.09.170
Mendelian randomization study to evaluate the effects of interleukin-6 signaling on four neurodegenerative diseases. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology BACKGROUND:Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 (IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS. METHODS:Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). RESULTS:We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR = 0.96, 95% CI 0.94-0.98, P = 1.69E-04), but not associated with the risk of AD (OR = 1.01, 95% CI 0.92-1.11, P = 0.835), PD (OR = 0.94, 95% CI 0.84-1.05, P = 0.261), or ALS (OR = 1.00, 95% CI 0.92-1.10, P = 0.9411). CONCLUSION:Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS. 10.1007/s10072-020-04381-x
A Mendelian Randomization-Based Causal Investigation on Bacterial Infection-Related Genes and Neurodegenerative Diseases. Studies in health technology and informatics Neurodegenerative diseases remain the most prevalent and unsolved health problems in human society, especially Alzheimer's disease (AD) and Parkinson's disease (PD). The pathogenesis, pathology, and potential clinical treatments of neurodegenerative diseases still require in-depth research. In the wake of the association between pandemics and a growing number of neurodegeneration patients, there has been growing speculation that infections are linked to AD and PD. The Aβ peptide is an important causal-related biomarker of AD and is reported to share structural and functional similarities with certain antimicrobial peptides, suggesting that it has a role in eliciting an immune response against microbes. But how neurodegeneration is related to bacterial chronic infection has not been thoroughly investigated. Using the data from genome-wide association studies (GWAS), we performed Mendelian Randomization (MR) and map 7 genes in multiple bacterial infection pathways as exposure, which show a significant association with the outcome of AD or PD. As co-verification, we perform Gene Set Enrichment Analysis (GSEA) on selected genetic variants incorporating their perturb-seq gene list (combining single-cell RNA-seq and CRISPR-based perturbations). We observed clustering of the differentially expressed genes (DEGs) in the upstream and downstream of AD and PD-related KEGG pathways, hence confirming their causal association with AD and PD and providing new perspectives on the true cause of neurodegeneration. 10.3233/SHTI230893
Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study. Frontiers in neuroscience Background:Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis. Methods:Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed. Results:Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed. Conclusion:Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors. 10.3389/fnins.2023.1321246
Exploring the bidirectional causal link between household income status and genetic susceptibility to neurological diseases: findings from a Mendelian randomization study. Frontiers in public health Objectives:Observational studies have revealed that socioeconomic status is associated with neurological disorders and aging. However, the potential causal effect between the two remains unclear. We therefore aimed to investigate the causal relationship between household income status and genetic susceptibility to neurological diseases using a bidirectional Mendelian randomization (MR) study. Methods:An MR study was conducted on a large-sample cohort of the European population pulled from a publicly available genome-wide association study dataset, using a random-effects inverse-variance weighting model as the main standard. MR-Egger regression, weighted median, and maximum likelihood estimation were also performed concurrently as supplements. A sensitivity analysis, consisting of a heterogeneity test and horizontal pleiotropy test, was performed using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to ensure the reliability of the conclusion. Results:The results suggested that higher household income tended to lower the risk of genetic susceptibility to Alzheimer's disease (odds ratio [OR]: 0.740, 95% confidence interval [CI] = 0.559-0.980, -value = 0.036) and ischemic stroke (OR: 0.801, 95% CI = 0.662-0.968, -value = 0.022). By contrast, higher household income tended to increase the risk of genetic susceptibility to Parkinson's disease (OR: 2.605, 95% CI = 1.413-4.802, -value = 0.002). No associations were evident for intracranial hemorrhage (OR: 1.002, 95% CI = 0.607-1.653, -value = 0.993), cerebral aneurysm (OR: 0.597, 95% CI = 0.243-1.465, -value = 0.260), subarachnoid hemorrhage (OR: 1.474, 95% CI = 0.699-3.110, -value = 0.308), or epilepsy (OR: 1.029, 95% CI = 0.662-1.600, -value = 0.899). The reverse MR study suggested no reverse causal relationship between neurological disorders and household income status. A sensitivity analysis verified the reliability of the results. Conclusion:Our results revealed that the populations with a superior household income exhibit an increased predisposition of genetic susceptibility to Parkinson's Disease, while demonstrating a potential decreased genetic susceptibility to ischemic stroke and Alzheimer's disease. 10.3389/fpubh.2023.1202747
Mapping the serum proteome to neurological diseases using whole genome sequencing. Nature communications Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities. 10.1038/s41467-021-27387-1
The impact of COVID-19 on pulmonary, neurological, and cardiac outcomes: evidence from a Mendelian randomization study. Frontiers in public health Background:Long COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2 infection that affects a significant proportion of individuals globally. It can manifest with a wide range of symptoms due to dysfunction of multiple organ systems including but not limited to cardiovascular, hematologic, neurological, gastrointestinal, and renal organs, revealed by observational studies. However, a causal association between the genetic predisposition to COVID-19 and many post-infective abnormalities in long COVID remain unclear. Methods:Here we employed Mendelian randomization (MR), a robust genetic epidemiological approach, to investigate the potential causal associations between genetic predisposition to COVID-19 and long COVID symptoms, namely pulmonary (pneumonia and airway infections including bronchitis, emphysema, asthma, and rhinitis), neurological (headache, depression, and Parkinson's disease), cardiac (heart failure and chest pain) diseases, and chronic fatigue. Using two-sample MR, we leveraged genetic data from a large COVID-19 genome-wide association study and various disorder-specific datasets. Results:This analysis revealed that a genetic predisposition to COVID-19 was significantly causally linked to an increased risk of developing pneumonia, airway infections, headache, and heart failure. It also showed a strong positive correlation with chronic fatigue, a frequently observed symptom in long COVID patients. However, our findings on Parkinson's disease, depression, and chest pain were inconclusive. Conclusion:Overall, these findings provide valuable insights into the genetic underpinnings of long COVID and its diverse range of symptoms. Understanding these causal associations may aid in better management and treatment of long COVID patients, thereby alleviating the substantial burden it poses on global health and socioeconomic systems. 10.3389/fpubh.2023.1303183
Clinical correlates of serum 25-hydroxyvitamin D in Parkinson's disease. Nutritional neuroscience BACKGROUND:Parkinson's disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. MATERIALS AND METHODS:We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls ( = 100) was included as a control group. RESULTS:PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure ( = .002) and vitamin D intake ( = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY,  = .035), worse clinical symptoms (UPDRS Part-III total score [ = .006] and dopaminergic [ = .033] and non-dopaminergic subscores [ = .001]) and greater global cognitive function impairment ( = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. CONCLUSION:: Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required. 10.1080/1028415X.2020.1840117
Lack of genetic evidence for NLRP3-inflammasome involvement in Parkinson's disease pathogenesis. medRxiv : the preprint server for health sciences Activation of the NLRP3-inflammasome has been implicated in Parkinson's disease based on and studies. Clinical trials targeting the NLRP3-inflammasome in Parkinson's disease are ongoing. However, the evidence supporting NLRP3's involvement in Parkinson's disease from human genetics data is limited. In this study, we conducted analyses of common and rare variants in NLRP3-inflammasome related genes in Parkinson's disease cohorts. We performed pathway-specific analyses using polygenic risk scores and studied potential causal associations using Mendelian randomization with the NLRP3 components and the cytokines IL-1β and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway polygenic risk score with Parkinson's disease. Mendelian randomization suggests that altering the expression of the NLRP3-inflammasome, IL-1β or IL-18, does not affect Parkinson's disease risk or progression. Therefore, our results do not support a role for the NLRP3-inflammasome in Parkinson's disease pathogenesis or as a target for drug development. 10.1101/2023.09.20.23295790
A Mendelian Randomization Approach Using 3-HMG-Coenzyme-A Reductase Gene Variation to Evaluate the Association of Statin-Induced Low-Density Lipoprotein Cholesterol Lowering With Noncardiovascular Disease Phenotypes. Liu Ge,Shi Mingjian,Mosley Jonathan D,Weng Chunhua,Zhang Yanfei,Lee Ming Ta Michael,Jarvik Gail P,Hakonarson Hakon,Namjou-Khales Bahram,Sleiman Patrick,Luo Yuan,Mentch Frank,Denny Joshua C,Linton MacRae F,Wei Wei-Qi,Stein C Michael,Feng QiPing JAMA network open Importance:Observational studies suggest that statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may be associated with beneficial effects in many noncardiovascular diseases. Objective:To construct a weighted HMG-CoA reductase (HMGCR) gene genetic risk score (GRS) using variants in the HMGCR gene affecting low-density lipoprotein cholesterol as an instrumental variable for mendelian randomization analyses to test associations with candidate noncardiovascular phenotypes previously associated with statin use in observational studies. Design, Setting, and Participants:This cohort study included 53 385 unrelated adults of European ancestry with genome-wide genotypes available from BioVU (a practice-based biobank, used for discovery) and 30 444 unrelated adults with European ancestry available in the Electronic Medical Records and Genomics (eMERGE; a research consortium that conducts genetic research using electronic medical records, used for replication). The study was conducted from February 6, 2015, through April 31, 2019; data analysis was performed from August 26, 2019, through December 22, 2020. Interventions:An HMGCR GRS was calculated. Main Outcomes and Measures:The association between the HMGCR GRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies. Results:Of the 53 385 individuals in BioVU, 29 958 (56.1%) were women; mean (SD) age was 59.9 (15.6) years. The finding between the HMGCR GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An HMGCR GRS equivalent to a 10-mg/dL decrease in the low-density lipoprotein cholesterol level was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.09; 95% CI, 1.04-1.15; P = 5.58 × 10-4). The HMGCR GRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58; P = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34; P = .008). Of the 30 444 individuals in eMERGE, 16 736 (55.0%) were women; mean (SD) age was 68.7 (15.4) years. The association between the HMGCR GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17; P = .02); however, the HMGCR GRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16; P = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41; P = .08) in the eMERGE cohort. Conclusions and Relevance:A mendelian randomization approach using variants in the HMGCR gene replicated the association between statin use and increased type 2 diabetes risk but provided no strong evidence for pleiotropic effects of statin-induced decrease of the low-density lipoprotein cholesterol level on other diseases. 10.1001/jamanetworkopen.2021.12820
Health Effects of Calcium: Evidence From Mendelian Randomization Studies. JBMR plus Calcium is widely used in conjunction with vitamin D to prevent osteoporosis. The use of calcium supplementation is also promoted for its potential benefits in lowering the risk for metabolic syndromes and cancers. However, the causal link between calcium and various health outcomes remains unclear. This review focuses on the evidence from 24 Mendelian randomization (MR) studies that were designed to minimize bias from confounding and reverse causation. These MR studies evaluated the effect of lifelong genetically higher serum calcium levels on various health outcomes. Overall, available MR studies found no conclusive effects of serum calcium levels on bone mineral density and fracture, ischemic stroke and heart failure, cancers, type 2 diabetes, Parkinson disease, or offspring birth weight. However, a higher serum calcium concentration was reported to have estimated causal effects on increased risks for coronary artery disease (especially myocardial infarction), migraine, renal colic, allergy/adverse effect of penicillin, and reduced risks for osteoarthrosis and osteoarthritis. In conclusion, supplementation of calcium in individuals from the general population is not predicted to influence the risk of most investigated diseases to date. Moreover, long-term high serum calcium concentrations may result in adverse health outcomes. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. 10.1002/jbm4.10542
Causal relationship between coffee intake and neurological diseases: a Mendelian randomization study. European journal of clinical nutrition BACKGROUND:Previous observational studies focused on the association of coffee consumption and neurological disease. However, it is not known whether these associations are causal. METHODS:We used Mendelian randomization (MR) study to assess the causal relationship of coffee intake with the risk of neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, and migraine. Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with coffee intake were used as instrumental variable (IV). Genetic instruments were stretched from the MRC-IEU (MRC Integrative Epidemiology Unit) analysis on the UK Biobank. We performed MR analyses using the inverse variance weighted (IVW) method as the main approach. Sensitivity analyses were further performed using MR-Egger and MR-PRESSO to assess the robustness. RESULTS:In the MR analysis, 40 SNPs were selected as IV, the F statistics for all SNPs ranged from 16 to 359. In IVW approach, our results provide genetic evidence supporting a potential causal association between coffee intake and a lower risk of migraine (OR = 0.528, 95% CI = 0.342-0.817, P = 0.004) and migraine with aura (OR = 0.374, 95% CI = 0.208-0.672, P = 0.001). However, we found no significant association between coffee intake and other neurological diseases along with their subtypes in this MR study. CONCLUSION:Using genetic data, our MR study found significant evidence supporting a causal association between coffee intake and migraine. This suggests that coffee consumption is likely a trigger or a prevention strategy for migraine. 10.1038/s41430-023-01355-y
Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome. PLoS genetics Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases. 10.1371/journal.pgen.1009224
Circulating S100B levels at birth and risk of six major neuropsychiatric or neurological disorders: a two-sample Mendelian Randomization Study. Translational psychiatry Circulating levels of the astrocytic marker S100B have been associated with risk of neuropsychiatric or neurological disorders. However, reported effects have been inconsistent, and no causal relations have yet been established. We applied two-sample Mendelian Randomization (MR) on the association statistics from genome-wide association studies (GWAS) for circulating S100B levels measured 5-7 days after birth (the iPSYCH sample) and in an older adult sample (mean age, 72.5 years; the Lothian sample), upon those derived from major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), autism spectral disorder (ASD), Alzheimer's disease (AD), and Parkinson's disease (PD). We studied the causal relations in the two S100B datasets for risk of these six neuropsychiatric disorders. MR suggested increased S100B levels 5-7 days after birth to causally increase the risk of MDD (OR = 1.014; 95%CI = 1.007-1.022; FDR-corrected p = 6.43×10). In older adults, MR suggested increased S100B levels to have a causal relation to the risk of BIP (OR = 1.075; 95%CI = 1.026-1.127; FDR-corrected p = 1.35×10). No significant causal relations were found for the other five disorders. We did not observe any evidence for reverse causality of these neuropsychiatric or neurological disorders on altered S100B levels. Sensitivity analyses using more stringent SNP-selection criteria and three alternative MR models suggested the results are robust. Altogether, our findings imply a small cause-effect relation for the previously reported associations of S100B and mood disorders. Such findings may provide a novel avenue for the diagnosis and management of disorders. 10.1038/s41398-023-02478-3
Assessment of causal factors for Parkinson's disease in European populations: A phenome-wide Mendelian randomisation analysis. Xue Zhe,Cheng Yinyin,Yu Qingyao,Wang Tiantian,Fan Chuanlong,Zou Zuquan,Zhang Xiaohong Asia Pacific journal of clinical nutrition BACKGROUND AND OBJECTIVES:To assess the causality of potentially modifiable factors, including lifestyle, nutrients, lipids, anthropometric traits, and inflammatory factors of Parkinson's disease (PD), genetic instruments for modifiable factors were identified from genome-wide association studies (GWAS). METHODS AND STUDY DESIGN:Genetic associations for PD (1,239 cases and 451,025 matched controls) were extracted from the UK Biobank GWAS summary statistics. The causal effects of modifiable factors on the risk of PD were estimated using the multiplicative random-effects inverse variance weighted method (IVW). RESULTS:In the IVW analysis, a decreased risk for PD was causally associated with genetically predicted smoking cessation (odds ratio 0.41, [95% confidence interval] 0.32-0.78; p<0.001), and higher bone mineral density (0.43, 0.38 -0.71; p<0.001), higher concentrations of vitamin B-12 (0.56, 0.43-0.91; p<0.001), docosahexenoic acid (0.52, 0.37-0.71; p<0.001), and sIL-6R (0.69, 0.58-0.75; p<0.001). Instead, analysis further supported the role of apolipoprotein (a) isoform size(1.67, 1.36-1.71; p<0.001), being a genetically morning person (2.18, 1.12-4.72; p<0.001), and number of cigarette smoking (1.05, 1.01-1.08; p<0.001) in contributing to the risk of developing PD. CONCLUSIONS:Our findings provide new evidence for the potential positive causal association of cigarette smoking number and apolipoprotein (a) isoform size and the inverse causal association of vitamin B-12, docosahexaenoic acid, smoking cessation, and soluble interleukin-6 receptor with PD, which contributes to the development of new interventions for PD. 10.6133/apjcn.202106_30(2).0018
Lipids, Apolipoproteins, and the Risk of Parkinson Disease. Fang Fang,Zhan Yiqiang,Hammar Niklas,Shen Xia,Wirdefeldt Karin,Walldius Göran,Mariosa Daniela Circulation research RATIONALE:A complete picture of the associations of the most common lipid fractions, including total cholesterol (TC), LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), triglycerides, and apolipoproteins, with the risk of Parkinson disease (PD), is lacking. OBJECTIVE:To assess the associations of lipids and apolipoproteins with the future risk of PD. METHODS AND RESULTS:In the AMORIS (Apolipoprotein-Related Mortality Risk) Study, we enrolled ≈600 000 participants during 1985 to 1996 in Stockholm, Sweden, with repeated measurements of TC, LDL-C, HDL-C, triglycerides, ApoB (apolipoprotein B), and ApoA-I (apolipoprotein A-I). The cohort was followed until the end of 2011, and incident cases of PD were identified through the Swedish Patient Register. We first used Cox models to estimate the associations of these biomarkers with later risk of PD. We further applied a Mendelian randomization analysis for TC, LDL-C, and triglycerides using the GWAS (Genome-wide association study) summary statistics from the public PD GWAS data and 23andMe PD cohorts with >800 000 individuals. One SD increase of TC was associated with a lower hazard of PD (hazard ratio, 0.90; 95% CI, 0.87-0.94). Similar associations were observed for LDL-C (hazard ratio, 0.93; 95% CI, 0.88-0.98), triglycerides (hazard ratio, 0.94; 95% CI, 0.90-0.97), and ApoB (hazard ratio, 0.91; 95% CI, 0.85-0.97). A clear dose-response relation was also noted when using these biomarkers as categorical variables. A causal inverse association of TC, LDL-C, and triglycerides with PD risk was further suggested by the Mendelian randomization analysis. CONCLUSIONS:Our findings reinforce that higher levels of TC, LDL-C, and triglycerides are associated with a lower future risk of PD and further suggest that these associations may be causal. The findings for ApoB in relation to PD risk are novel, and whether such association is causal needs to be examined. 10.1161/CIRCRESAHA.119.314929
Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease. NPJ Parkinson's disease Common and rare variants in the LRRK2 locus are associated with Parkinson's disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways. 10.1038/s41531-023-00555-4
Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease. NPJ Parkinson's disease Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities. 10.1038/s41531-023-00496-y
Lack of Causal Effects or Genetic Correlation between Restless Legs Syndrome and Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Epidemiological studies have reported an association between Parkinson's disease (PD) and restless legs syndrome. OBJECTIVES:We aimed to use genetic data to study whether these 2 disorders are causally linked or share genetic architecture. METHODS:We performed two-sample Mendelian randomization and linkage disequilibrium score regression using summary statistics from recent genome-wide meta-analyses of PD and restless legs syndrome. RESULTS:We found no evidence for a causal relationship between restless legs syndrome (as the exposure) and PD (as the outcome, inverse variance-weighted; b = -0.003, SE = 0.031, P = 0.916; F statistic = 217.5). Reverse Mendelian randomization also did not demonstrate any causal effect of PD on restless legs syndrome (inverse variance-weighted; b = -0.012, SE = 0.023, P = 0.592; F statistic = 191.7). Linkage disequilibrium score regression analysis demonstrated lack of genetic correlation between restless legs syndrome and PD (rg = -0.028, SE = 0.042, P = 0.507). CONCLUSIONS:There was no evidence for a causal relationship or genetic correlation between restless legs syndrome and PD. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants. © 2021 International Parkinson and Movement Disorder Society. 10.1002/mds.28640
Hyperuricemia, Gout, and the Brain-an Update. Latourte Augustin,Dumurgier Julien,Paquet Claire,Richette Pascal Current rheumatology reports PURPOSE OF REVIEW:This review aims to summarize recent evidence regarding the complex relationship between uric acid (UA), gout, and brain diseases. RECENT FINDINGS:Observational studies have suggested that patients with hyperuricemia or gout might have a decreased risk of neurodegenerative diseases. Conversely, they may be at increased risk of cerebrovascular disease. Mendelian randomization (MR) studies use a genetic score as an instrumental variable to address the causality of the association between a risk factor (here, UA or gout) and an outcome. So far, MR analyses do not support a causal relationship of UA or gout with Alzheimer's disease and dementia, and of UA with Parkinson's disease or stroke. Observation studies indicate a U-shaped association between UA and brain diseases, but MR studies do not support that this association is causal. Further studies should address the causal role of gout as well as the impact of urate-lowering therapy on these outcomes. 10.1007/s11926-021-01050-6
Genetic analysis of Mendelian mutations in a large UK population-based Parkinson's disease study. Brain : a journal of neurology Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors. 10.1093/brain/awz191
Gene-environment interaction and Mendelian randomisation. Kolber P,Krüger R Revue neurologique Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals) and the interaction with genetic susceptibility factors (summarized in the concept of impaired xenobiotic metabolism) are believed to play a major role in the mechanisms of neurodegeneration. Beside of the classical association studies (e.g. genome-wide association studies), a novel approach to investigate environmental risk factors are Mendelian randomisation studies. This review explores the gene-environment interaction and the gain of Mendelian randomisation studies in assessing causalities of modifiable risk factors for PD. 10.1016/j.neurol.2019.04.010
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19. Nature Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown to be highly efficient for discovery of genetic associations. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). 10.1038/s41586-023-06034-3
Inflammatory bowel disease and risk of Parkinson's disease: evidence from a meta-analysis of 14 studies involving more than 13.4 million individuals. Frontiers in medicine Background:The relationship between inflammatory bowel disease (IBD) and the risk of Parkinson's Disease (PD) has been investigated in several epidemiological studies. However, the results of these studies were inconclusive and inconsistent. We evaluated the potential relationship between IBD and PD risk by a meta-analysis. Methods:Search the electronic databases PubMed, Embase and Cochrane databases from inception to November 30, 2022, to identify relevant studies that assess the risk of PD in patients with IBD. The cohort, cross-sectional, mendelian randomization and case-control studies that reported risk estimates of PD and IBD were included in our analysis. The random-effect model and fixed-effects model were used to calculate the summary relative risks (RRs) with 95% confidence intervals (CIs). Results:In total, 14 studies (nine cohort studies, two cross-sectional studies, two mendelian randomization studies and one case-control study) involving more than 13.4 million individuals were analyzed in our analysis. Our results suggested that the risk of PD in IBD patients is moderately increased, with the pooled RR was 1.17 (95% CI: 1.03-1.33, = 0.019). Omit of any single study from this analysis had little effect on the combined risk estimate. No evidence of publication bias was found. In the subgroup analysis, the combined RR was 1.04 (95% CI: 0.96, 1.12, = 0.311) for Crohn's disease (CD), and 1.18 (95% CI: 1.06, 1.31, = 0.002) for ulcerative colitis (UC). In addition, a significant association was identified in patients with IBD aged ≥ 60 years (RR = 1.22; 95% CI: 1.06-1.41, = 0.007), but not in age < 60 years (RR = 1.19; 95% CI: 0.58-2.41, = 0.639). Meanwhile, the meta-analysis results suggested a protective role for IBD medication use against PD development, with the RR was 0.88 (95% CI: 0.74, 1.04, = 0.126). Conclusion:Our results indicated that patients with IBD had a moderately higher risk of PD compared to non-IBD individuals. Patients with IBD should be aware of the potential risks for PD, especially who were ≥ 60 years old. 10.3389/fmed.2023.1137366
Protective effect of antihypertensive drugs on the risk of Parkinson's disease lacks causal evidence from mendelian randomization. Frontiers in pharmacology Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson's disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD. Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes. In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by "encoding region-based method" for β-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO. Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology. 10.3389/fphar.2023.1107248
Gut microbiota, circulating cytokines and dementia: a Mendelian randomization study. Journal of neuroinflammation BACKGROUND:Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear. METHODS:Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia. RESULTS:There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors. CONCLUSIONS:Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia. 10.1186/s12974-023-02999-0
The role of plasma cortisol in dementia, epilepsy, and multiple sclerosis: A Mendelian randomization study. Frontiers in endocrinology Background:Many clinical studies have shown a correlation between plasma cortisol and neurological disorders. This study explored the causal relationship between plasma cortisol and dementia, epilepsy and multiple sclerosis based on Mendelian randomization (MR) method. Methods:Data were taken from the summary statistics of a genome-wide association study, FinnGen consortium and United Kingdom Biobank. Dementia, epilepsy, and multiple sclerosis were used as outcomes, and genetic variants associated with plasma cortisol were used as instrumental variables. The main analysis was performed using the inverse variance weighted method, and the results were assessed according to the odds ratio (OR) and 95% confidence interval. Heterogeneity tests, pleiotropy tests, and leave-one-out method were conducted to evaluate the stability and accuracy of the results. Results:In two-sample MR analysis, the inverse variance weighted method showed that plasma cortisol was associated with Alzheimer's disease (AD) [odds ratio (95% confidence interval) = 0.99 (0.98-1.00), = 0.025], vascular dementia (VaD) [odds ratio (95% confidence interval) = 2.02 (1.00-4.05), = 0.049)], Parkinson's disease with dementia (PDD) [odds ratio (95% confidence interval) = 0.24 (0.07-0.82), = 0.023] and epilepsy [odds ratio (95% confidence interval) = 2.00 (1.03-3.91), = 0.042]. There were no statistically significant associations between plasma cortisol and dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and multiple sclerosis. Conclusion:This study demonstrates that plasma cortisol increase the incidence rates of epilepsy and VaD and decrease the incidence rates of AD and PDD. Monitoring plasma cortisol concentrations in clinical practice can help prevent diseases, such as AD, PDD, VaD and epilepsy. 10.3389/fendo.2023.1107780
Association Between Rheumatoid Arthritis and Risk of Parkinson's Disease: A Meta-Analysis and Systematic Review. Frontiers in neurology Background:Rheumatoid arthritis (RA) and Parkinson's disease (PD) are two common chronic diseases worldwide, and any potential link between the two would significantly impact public health practice. Considering the current inconsistent evidence, we conducted a meta-analysis and systematic review to examine the risk of PD in patients with RA. Methods:Two investigators (DL and XH) conducted a comprehensive search of PubMed, Embase, and Web of Science using medical subject headings terms combined with free words to identify relevant papers published from inception through December 31, 2021. All studies that explored the relationship between RA and PD were included for quantitative analysis and qualitative review. Random- and fixed-effects models were used to pool the risk ratios (RRs) of PD in patients with RA. The Newcastle-Ottawa scale was used to assess the quality of included studies. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guideline. Results:Four population-based studies involving 353,246 patients and one Mendelian randomized study were included in our study. The pooled result showed a significantly reduced risk of PD in patients with RA than in the general population (RR = 0.74, 95% CI: 0.56-0.98, = 0.034). No apparent effects of gender, age, region, follow-up time, or study design on PD risk were observed. Sensitivity analysis showed that pooled results were relatively stable, and no publication bias was detected. The Mendelian randomization study indicated a significant inverse association between RA and PD (genetic correlation: -0.10, = 0.0033) and that each one standard deviation increase in the risk of RA was significantly associated with a lower risk of PD. Of note, the current study is limited by the relatively small number of included studies and unmeasured confounding factors, especially for RA-related anti-inflammatory agents. Conclusions:This study supports that people with RA had a lower PD risk than those without RA. Further studies are needed to explore the underlying molecular mechanisms of the interaction between the two diseases. 10.3389/fneur.2022.885179
Low LDL cholesterol, and genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. Benn Marianne,Nordestgaard Børge G,Frikke-Schmidt Ruth,Tybjærg-Hansen Anne BMJ (Clinical research ed.)  To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis( and 3-hydroxy-3-methylglutaryl-CoA reductase (), respectively) is associated with a high risk of Alzheimer's disease, vascular dementia, any dementia, and Parkinson's disease in the general population. Mendelian randomisation study. Copenhagen General Population Study and Copenhagen City Heart Study. 111 194 individuals from the Danish general population. Risk of Alzheimer's disease, vascular dementia, all dementia, and Parkinson's disease. In observational analyses, the multifactorially adjusted hazard ratio for Parkinson's disease in participants with an LDL cholesterol level <1.8 mmol/L versus ≥4.0 mmol/L was 1.70 (95% confidence interval 1.03 to 2.79), whereas the corresponding hazard ratios for Alzheimer's disease, vascular dementia, or any dementia did not differ from 1.0. and variants combined were associated with a 9.3% lower LDL cholesterol level. In genetic, causal analyses adjusted for age, sex, and year of birth, the risk ratios for a lifelong 1 mmol/L lower LDL cholesterol level were 0.57 (0.27 to 1.17) for Alzheimer's disease, 0.81 (0.34 to 1.89) for vascular dementia, 0.66 (0.34 to 1.26) for any dementia, and 1.02 (0.26 to 4.00) for Parkinson's disease. Summary level data from the International Genomics of Alzheimer's Project using Egger Mendelian randomisation analysis gave a risk ratio for Alzheimer's disease of 0.24 (0.02 to 2.79) for 26 and variants, and of 0.64 (0.52 to 0.79) for 380 variants of LDL cholesterol level lowering. Low LDL cholesterol levels due to and variants had no causal effect on high risk of Alzheimer's disease, vascular dementia, any dementia, or Parkinson's disease; however, low LDL cholesterol levels may have a causal effect in reducing the risk of Alzheimer's disease. 10.1136/bmj.j1648
Investigation of the causal relationship between osteocalcin and dementia: A Mendelian randomization study. Heliyon Objective:Basic medical studies have reported an improved effect of osteocalcin on cognition. We explored the causal link between osteocalcin and dementia via the implementation of Mendelian randomization methodology. Methods:Genome-wide association studies were employed to identify single nucleotide polymorphisms (SNPs) showing significant correlations with osteocalcin. Subsequently, A two-sample Mendelian randomization analysis was conducted utilizing the inverse-variance-weighted (IVW) technique to assess the causal relationship between osteocalcin and various types of dementia, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD), and vascular dementia (VD). This approach aimed to minimize potential sources of confounding bias and provide more robust results. Multivariable MR (MVMR) analysis was conducted to adjust for potential genetic pleiotropy. Results:The study employed three SNPs, namely rs71631868, rs9271374, and rs116843408, as genetic tools to evaluate the causal association of osteocalcin with dementia. The IVW analysis indicated that osteocalcin may have a potential protective effect against AD with an odds ratio (OR) of 0.790 (95 % CI: 0.688-0.906; P < 0.001). However, no significant relationship was observed between osteocalcin and other types of dementia. Furthermore, the MVMR analysis indicated that the impact of osteocalcin on AD remained consistent even after adjusting for age-related macular degeneration and Type 2 diabetes with an OR of 0.856 (95 % CI: 0.744-0.985; P = 0.030). Conclusions:Our findings provide important insights into the role of osteocalcin in the pathogenesis of AD. Future research is required to clarify the underlying mechanisms and their clinical applications. 10.1016/j.heliyon.2023.e21073
Causal Relationships Between Osteoarthritis and Senile Central Nerve System Dysfunction: A Bidirectional Two-Sample Mendelian Randomization Study. Cai Yuanqing,Zhang Guangyang,Liang Jialin,Jing Zhaopu,Zhang Rupeng,Lv Leifeng,Dang Xiaoqian Frontiers in aging neuroscience Background:The relationship between osteoarthritis (OA) and senile central nervous system dysfunctions (CNSDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and ischemic stroke (IS) has gradually attracted attention. At present, the causal relationship between OA and CNSD remains unclear. The aim of this study was to assess the causal effects of CNSD and OA using Mendelian randomization (MR). Methods:Genome-wide association study summary data for CNSD and OA were obtained. Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs), and significant ( < 5.0 × 10) and independent ( < 0.1) SNPs were extracted for bidirectional MR analysis. Inverse variance weighted (IVW) was used to assess these causal relationships. The results are reported as odds ratios (ORs). Subsequently, heterogeneity was tested using the Cochran's test, pleiotropy was tested using the MR-Egger intercept, and sensitivity analysis was performed using the leave-one-out sensitivity test. Results:The MR results of the causal relationship between PD and OA showed that there was a positive causal effect of OA on PD, which was estimated by IVW (OR = 1.194, 95%CI = 1.036, 1.378; = 0.0144). Moreover, the MR analysis by IVW also showed that IS had a positive effect on OA (OR = 1.033, 95%CI = 1.002, 1.066; = 0.0355). These results are reliable and stable, as confirmed by sensitivity tests. Conclusion:This study showed a positive causal effect of OA on PD, but there was a null effect of OA on AD and OA on IS. 10.3389/fnagi.2021.793023
Education, intelligence, and amyotrophic lateral sclerosis: A Mendelian randomization study. Zhang Linjing,Tang Lu,Xia Kailin,Huang Tao,Fan Dongsheng Annals of clinical and translational neurology OBJECTIVE:To systematically investigate causal relationships between educational attainment, cognitive-related phenotypes, and amyotrophic lateral sclerosis (ALS). METHODS:Summary statistics from genome-wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two-sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them. RESULTS:Genetically predisposition to longer educational attainment and harder math class taken were associated with significantly lower statistical odds ratio of ALS. For per year increase in education completed there was a 21% lower (95% confidence interval [CI] = 27-14%) in risk for ALS. For per 1-SD increase in the highest math class taken obtained there was a 19% lower (95% CI = 9-28%) in risk for ALS. Genetically predisposition to math ability, cognitive performance, and intelligence did not decrease the risk of ALS. INTERPRETATION:This study provides genetic support for a causal association between higher educational attainment and a lower risk of ALS. The genes related to these phenotypes are involved in almost all aspects of neuron-to-neuron communication. ALS patients are occasionally accompanied by varying degrees of cognitive impairment. People with greater cognitive reserve may be better able to offset damages of degenerative brain changes associated with dementia or other brain diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or ALS. 10.1002/acn3.51156
Absence of causal relationship between Parkinson's disease and subsequent prostate cancer: evidence from meta-analysis and Mendelian randomization studies. Frontiers in oncology Background:Numerous observational studies have investigated the risk of prostate cancer (PCa) in patients diagnosed with Parkinson's Disease (PD). However, the existence of a definitive association remains uncertain. Methods:Systematic searches were performed on PubMed, Web of Science, Scopus, and Google Scholar for studies published up to October 1, 2023. For Mendelian randomized (MR) causal inference, we employed pooled data from the IPDGC and PRACTICAL Consortium. The inverse variance weighted (IVW) method served as the principal technique for estimating odds ratios (ORs) and 95% confidence intervals (CIs) for the associations under investigation. Results:Cumulative analysis of nine studies revealed no significant association between patients diagnosed with PD and the subsequent incidence of PCa ([relative ratio] RR = 0.89, 95%CI = 0.73 to 1.08, P = 0.237). However, subgroup analyses indicated a reduced occurrence of PCa in Caucasian patients with PD (RR = 0.81, 95%CI = 0.69 to 0.95, P = 0.011). MR analyses failed to establish a significant link between increased genetic susceptibility to PD and the risk of PCa (IVW OR = 1.025, 95%CI = 0.997 to 1.054, P = 0.082). Sensitivity analyses further corroborated the robustness of these results. Conclusion:Both observational meta-analysis and MR analysis based on genetic variation do not support an association between PD patients and the subsequent risk of PCa. Further research is warranted to unravel the potential underlying mechanisms linking these two diseases. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023473527. 10.3389/fonc.2023.1323812
Mendelian randomization of serum urate and parkinson disease progression. Simon Kelly Claire,Eberly Shirley,Gao Xiang,Oakes David,Tanner Caroline M,Shoulson Ira,Fahn Stanley,Schwarzschild Michael A,Ascherio Alberto, Annals of neurology OBJECTIVE:Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. METHODS:The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. RESULTS:Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. INTERPRETATION:This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels. 10.1002/ana.24281
Assessing the association between white matter lesions and Parkinson's disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology BACKGROUND:The association between white matter (WM) lesions and Parkinson's disease (PD) was not fully established. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect between white matter lesions and PD. METHODS:We performed a bidirectional two-sample Mendelian randomization (MR) study to investigate the association between three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with PD (N = 482,730) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods were used to evaluate the causal estimate. RESULTS:Significant evidence was suggested that higher MD was associated with a higher PD risk (OR = 1.049, 95% CI = 1.018-1.081, p = 0.022) when the outlier was removed using MR-PRESSO method. Moreover, genetically predicted PD was associated with a lower WMH load (IVW β = - 0.047, 95% CI = - 0.085 to - 0.009, p = 0.016) and a higher FA (β = 0.185, 95% CI = 0.021-0.349, p = 0.027). No evidence of pleiotropy was found using MR-Egger intercept. CONCLUSION:Our findings provided genetic support that white matter microstructural integrity lesions might increase the risk of PD. However, genetically predicted PD was potentially associated with a lower load of white matter lesions. 10.1007/s10072-022-06494-x
Nonselective beta-adrenoceptor blocker use and risk of Parkinson's disease: from multiple real-world evidence. BMC medicine BACKGROUND:People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD. METHODS:We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD. RESULTS:In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33-4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19-2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04-2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73-0.99). CONCLUSIONS:Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments. 10.1186/s12916-023-03122-z
Identification of Parkinson's Disease-Causing Genes via Omics Data. Cui Xinran,Xu Chen,Zhang Liyuan,Wang Yadong Frontiers in genetics Parkinson's disease (PD) is the second most frequent neurogenic disease after Alzheimer's disease. The clinical manifestations include mostly motor disorders, such as bradykinesia, myotonia, and static tremors. Since the cause of this pathological features remain unclear, there is currently no radical treatment for PD. Environmental and genetic factors are thought to contribute to the pathology of PD. To identify the genetic factors, some studies employed the Genome-Wide Association Studies (GWAS) method and detected certain genes closely related to PD. However, the functions of these gene mutants in the development of PD are unknown. Combining GWAS and expression Quantitative Trait Loci (eQTL) analysis, the biological meaning of mutation could be explained to some extent. Therefore, the present investigation used Summary data-based Mendelian Randomization (SMR) analysis to integrate of two PD GWAS datasets and four eQTL datasets with the objective of identifying casual genes. Using this strategy, we found six Single Nucleotide Polymorphism (SNP) loci which could cause the development of PD through altering the susceptibility gene expression, and three risk genes: Synuclein Alpha (SNCA), Mitochondrial Poly(A) Polymerase (MTPAP), and RP11-305E6.4. We proved the accuracy of results through case studies and inferred the functions of these genes in PD. Overall, this study provides insights into the genetic mechanism behind PD, which is crucial for the study of the development of this disease and its diagnosis and treatment. 10.3389/fgene.2021.712164
Causal Relationship between Parkinson's Disease with Heart and Vascular Disease: A Two-Sample Mendelian Randomization Study. European neurology INTRODUCTION:The aim of this study was to investigate the causal relationship between Parkinson's disease (PD) and myocardial infarction (MI), atrial fibrillation and flutter (AF), and venous thromboembolism (VTE) by Mendelian randomization (MR) analysis. METHODS:By using data from publicly available genome-wide association studies from databases, single nucleotide polymorphisms were screened as instrumental variables, and the MR analysis was finished by inverse-variance weighted (IVW), MR-egger, weighted median methods. RESULTS:The primary IVW method showed a negative association between genetically predicted PD and risk of MI (OR = 0.9989; 95% CI: 0.9980-0.9998; p = 0.02). However, PD was not significantly associated with AF or VTE. CONCLUSION:This study suggests a negative association between PD with MI, which implies that PD has a protective effect on MI. 10.1159/000536484
No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study. Larsson Susanna C,Singleton Andrew B,Nalls Mike A,Richards J Brent, Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Observational studies have found that relative to healthy controls, patients with Parkinson's disease have lower circulating concentrations of 25-hydroxyvitamin D, a clinical biomarker of vitamin D status. However, the causality of this association is uncertain. We undertook a Mendelian randomization study to investigate whether genetically decreased 25-hydroxyvitamin D concentrations are associated with PD to minimize confounding and prevent bias because of reverse causation. METHODS:As instrumental variables for the Mendelian randomization analysis, we used 4 single-nucleotide polymorphisms that affect 25-hydroxyvitamin D concentrations (rs2282679 in GC, rs12785878 near DHCR7, rs10741657 near CYP2R1, and rs6013897 near CYP24A1). Summary effect size estimates of the 4 single-nucleotide polymorphisms on PD were obtained from the International Parkinson's Disease Genomics Consortium (including 5333 PD cases and 12,019 controls). The estimates of the 4 single-nucleotide polymorphisms were combined using an inverse-variance weighted meta-analysis. RESULTS:Of the 4 single-nucleotide polymorphisms associated with 25-hydroxyvitamin D concentrations, one (rs6013897 in CYP24A1) was associated with PD (odds ratio per 25-hydroxyvitamin D-decreasing allele, 1.09; 95% confidence interval, 1.02-1.16; P = 0.008), whereas no association was observed with the other 3 single-nucleotide polymorphisms (P > 0.23). The odds ratio of PD per genetically predicted 10% lower 25-hydroxyvitamin D concentration, based on the 4 single-nucleotide polymorphisms, was 0.98 (95% confidence interval, 0.93-1.04; P = 0.56). CONCLUSIONS:This Mendelian randomization study provides no clear support that lowered 25-hydroxyvitamin D concentration is causally associated with risk of PD. © 2017 International Parkinson and Movement Disorder Society. 10.1002/mds.27069
Immunosuppressants contribute to a reduced risk of Parkinson's disease in rheumatoid arthritis. International journal of epidemiology BACKGROUND:Observational studies have suggested a decreased risk of Parkinson's disease (PD) in patients with rheumatoid arthritis (RA). However, the results are controversial and the biological mechanism underlying this effect remains largely unknown. METHODS:The effect sizes of five observational studies were summarized to determine the association between RA and PD. A two-step Mendelian randomization (TSMR) analysis was conducted using genome-wide association studies data sets of RA, PD and prescription of non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants (IS) and glucocorticoids (GC). A multivariable MR (MVMR) was also performed to verify the impact of prescription history on PD risk. RESULTS:Integrated data from observational studies showed that RA was associated with a decreased risk of PD in the European population (effect size = -0.38, P = 0.004). We found that genetically predicted RA was correlated with a decreased risk of PD [odds ratio (OR) = 0.91, P = 0.007]. In the TSMR, RA patients tended to have an increased prescription of GC (OR = 1.16, P = 2.96e - 07) and IS (OR = 1.77, P = 5.58e - 64), which reduced the risk of PD (GC: OR = 0.86, P = 0.0270; IS: OR = 0.82, P = 0.0277), respectively. Further MVMR analysis demonstrated that only IS was linked to a decreased risk of PD (OR = 0.86, P = 0.004). CONCLUSION:This work clarified that patients with RA had a decreased risk of PD, which was partially attributed to the use of IS in RA patients but not GC or NSAIDs. 10.1093/ije/dyac085
Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease. Annals of neurology OBJECTIVES:Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis. METHODS:We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations. RESULTS:After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07-1.32, p = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; OR = 1.09, 95% CI = 1.01-1.18, p = 0.02). INTERPRETATION:We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021;89:803-812. 10.1002/ana.26034
Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study. PLoS medicine BACKGROUND:Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. METHODS AND FINDINGS:We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron. CONCLUSIONS:Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. 10.1371/journal.pmed.1001462
Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood. Biological psychiatry BACKGROUND:Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. METHODS:We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. RESULTS:Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. CONCLUSIONS:Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets. 10.1016/j.biopsych.2022.11.002
Quantitative and causal analysis for inflammatory genes and the risk of Parkinson's disease. Frontiers in immunology Background:The dysfunction of immune system and inflammation contribute to the Parkinson's disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk. Methods:Standard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them. Results:We included 36 variants in 18 genes for final pooled analysis. As a result, rs1800795, rs1799964, rs854560, rs3892097, rs660895, rs11931532, rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in and were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by ) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by ) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]). Conclusion:Several polymorphisms from inflammatory genes of were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis. 10.3389/fimmu.2023.1119315
Potential Protective Link Between Type I Diabetes and Parkinson's Disease Risk and Progression. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Epidemiological studies suggested an association between Parkinson's disease (PD) and type 2 diabetes, but less is known about type 1 diabetes (T1D) and PD. OBJECTIVE:This study sought to explore the association between T1D and PD. METHODS:We used Mendelian randomization, linkage disequilibrium score regression, and multi-tissue transcriptome-wide analysis to examine the association between PD and T1D. RESULTS:Mendelian randomization showed a potentially protective role of T1D for PD risk (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = 0.039), as well as motor (OR, 0.94; 95% CI, 0.88-0.99; P = 0.044) and cognitive progression (OR, 1.50; 95% CI, 1.08-2.09; P = 0.015). We further found a negative genetic correlation between T1D and PD (rg = -0.17; P = 0.016), and we identified eight genes in cross-tissue transcriptome-wide analysis that were associated with both traits. CONCLUSIONS:Our results suggest a potential genetic link between T1D and PD risk and progression. Larger comprehensive epidemiological and genetic studies are required to validate our findings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.29424
Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease. 10.1038/s41586-022-04576-6
Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nature genetics Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. 10.1038/s41588-021-00973-1
Causal relationships between type 1 diabetes mellitus and Alzheimer's disease and Parkinson's disease: a bidirectional two-sample Mendelian randomization study. European journal of medical research BACKGROUND:Previous compelling evidence suggests an association between Type 2 diabetes (T2D) and neurodegenerative diseases. However, it remains uncertain whether Type 1 diabetes mellitus (T1DM) exerts a causal influence on the risk of Alzheimer's disease (AD) and Parkinson's disease (PD). Consequently, this study employed a bidirectional two-sample Mendelian Randomization (MR) approach to investigate the causal relationship between T1DM and the genetic susceptibility to AD and PD. METHODS:We utilized large-scale cohorts derived from publicly available genome-wide association study datasets involving European populations to perform MR analyses. The primary analytical method employed was the inverse-variance weighted (IVW) approach. Furthermore, sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, were carried out using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to enhance the robustness of our conclusions. RESULTS:Using the IVW-based method, the MR analysis indicated no significant association between genetically determined T1DM and AD (OR = 0.984, 95% CI: 0.958-1.011, p = 0.247). Conversely, T1DM appeared to be associated with a reduced risk of genetic susceptibility to PD (IVW: OR = 0.958, 95% CI: 0.928-0.989, p = 0.001). In the reverse direction, no evidence of reverse causality was observed between AD (OR = 1.010, 95% CI: 0.911-1.116, p = 0.881) or PD (OR = 1.164, 95% CI: 0.686-2.025, p = 0.5202) and T1DM. Additionally, our analysis found no indications of the results being influenced by horizontal pleiotropy. CONCLUSION:This MR study reveals that T1DM is associated with a reduced genetic susceptibility to PD, whereas no significant genetic susceptibility is observed between T1DM and AD. These findings suggest that T1DM may have a distinct role in the development of neurodegenerative diseases compared to T2D. Further investigations are warranted to elucidate the underlying mechanisms and provide a more comprehensive understanding of this relationship. 10.1186/s40001-023-01628-z
Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. OBJECTIVE:We used MR to assess the association between age at menopause and age at menarche with PD risk. METHODS:We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. RESULTS:For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29). CONCLUSIONS:A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society. 10.1002/mds.28760
Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear. OBJECTIVE:We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD. METHODS:Leveraging the largest genome-wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome-wide cross-trait analysis via Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association to identify specific single-nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome-wide association study via functional summary-based imputation and joint-tissue imputation to explore comorbid genes, followed by pathway enrichment analysis. RESULTS:We found that PD positively correlates with ALS (r  = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03-1.15, P = 3.00 × 10 ). We identified nine single-nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome-wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977). CONCLUSIONS:Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society. 10.1002/mds.29572
Exploring the causal relationship between B lymphocytes and Parkinson's disease: a bidirectional, two-sample Mendelian randomization study. Scientific reports Parkinson's disease (PD) is a neurodegenerative disorder with extensive involvement of motor symptoms, imposing a heavy economic burden on patients and society. B lymphocytes, a group of immune cells associated with humoral immunity, have been shown to be involved in the pathogenesis of PD. However, the causal relationship and potential pathogenic effects of B cell in PD remain unclear. Based on the three core hypotheses of the Mendelian randomization (MR) study, we explored causal associations between 190 B-cell immunological traits and 482,730 European individuals (Ncase = 33,674, Ncontrol = 449,056) from genome wide association studies by means of the two-sample bidirectional MR method. The inverse‑variance weighted method was selected as the main approach when conducting MR analysis. Finally, the results were verified by the heterogeneity and horizontal pleiotropy analyses. Five B-cell immunological phenotypes were nominally associated with PD at the significance threshold of P < 0.05. Concretely, IgD + CD38- B cell %lymphocyte (OR 1.052, 95% CI 1.001-1.106, P = 0.046), CD20 on IgD- CD24- B cell (OR 1.060, 95% CI 1.005-1.117, P = 0.032), CD38 on IgD+ CD24- B cell (OR 1.113, 95% CI 1.028-1.206, P = 0.009), and BAFF-R on CD20- B cell (OR 1.093, 95% CI 1.010-1.184, P = 0.027) were identified as risk factors for PD. Instead, CD38 on Plasma Blast-Plasma Cell (OR 0.894, 95% CI 0.802-0.996, P = 0.043) was proved to be protective. However, there is no statistically significant correlation between B cell and PD after Bonferroni correction. The results of reverse MR were negative, avoiding the reverse causal effects. Eventually, the association results were identified as stable across several sensitivity analyses. Briefly, our study might demonstrate the key factor of B cells in PD. Further studies are warranted to clarify the associations for early identification and immunotherapeutic development in PD patients. 10.1038/s41598-024-53287-7
Genetic predisposition to neurodegenerative diseases and risk of stroke: A Mendelian randomization study. Frontiers in neuroscience Background:Traditional epidemiological studies suggested that Neurodegenerative diseases (ND) might correlate with stroke. We intend to explore whether the two most common neurodegenerative diseases [Alzheimer's disease (AD) and Parkinson's disease (PD)] are causally associated with stroke and its subtypes. Methods:Two-sample Mendelian Randomization (MR) method was used to explore the causal relationships. Candidate genetic instrumental variables (IVs) for AD and PD were collected from the genome-wide association studies (GWAS) in European populations. The inverse-variance weighted (IVW) method was the primary method of MR analysis, and the weighted median method was supplementary. In addition, the MR-Egger method and the MR-PRESSO test were used as well. Results:We found no causal effects of AD on stroke, Ischemic stroke (IS), or Intracerebral hemorrhage (ICH). As for PD and stroke, our preliminary results showed PD could causally influence the risk of stroke [odds ratio (OR): 1.04; 95% confidence interval (CI): 1.02-1.07; = 0.001 by the IVW method], although the alternative method did not support this result. We identified the positive causal relationship between PD and the risk of IS (OR = 1.04; 95% CI: 1.02-1.07; = 0.001 by the IVW method), and the alternative MR methods produced similar results. The present study found there was no causal relationship between PD and ICH. Conclusion:This study found a causal relationship between genetic susceptibility to PD and the incidence of stroke (especially IS) in the European population; however, there was no causal relation between AD and stroke risk. 10.3389/fnins.2022.995045
Is There an Association Between Parkinson's Disease and Periodontitis? A Systematic Review and Meta-Analysis. Journal of Parkinson's disease BACKGROUND:Multiple observational studies have yielded controversial results regarding the association between Parkinson's disease (PD) and periodontitis. OBJECTIVE:This systematic review and meta-analysis was conducted to ascertain their bidirectional relationship. METHODS:A literature search for relevant studies was performed in PubMed, EMBASE, the Cochrane Library, and Web of Science databases from inception to December 19, 2022. Effect sizes (ES) with 95% confidence intervals were pooled under the random-effects model. Then, leave-one-out sensitivity analysis and contour-enhanced funnel plot were applied to assess the stability of the results. RESULTS:A total of 34 studies and 24 studies were included for systematic review and quantitative meta-analysis, respectively. Pooled ES indicated that periodontitis was not significantly associated with PD risk (HR = 1.13, 95% CI 0.88-1.45, n = 3; OR = 1.94, 95% CI 0.55-6.90, n = 7), while the Mendelian randomization study revealed no association between PD and periodontitis risk (coefficient [B] = -0.0001, standard error = 0.0001, p = 0.19). Furthermore, PD patients exhibited higher levels of periodontal pocket depth (SMD = 1.10, 95% CI 0.53-1.67), clinical attachment level (SMD = 1.40, 95% CI 0.55-2.26), plaque index (SMD = 0.81, 95% CI 0.22-1.39), and Oral Health Impact Profile-14 score (SMD = 0.91, 95% CI 0.33-1.49) compared to healthy controls. CONCLUSIONS:Our meta-analysis identified no bidirectional association between PD risk and periodontitis risk, though the prevalence of periodontitis and poorer oral status was higher in PD patients. 10.3233/JPD-230059
No Evidence for a Causal Relationship Between Cancers and Parkinson's Disease. Journal of Parkinson's disease BACKGROUND:Epidemiological data suggest that cancer patients have a reduced risk of subsequent Parkinson's disease (PD) development, but the prevalence of PD in melanoma patients is often reported to be increased. Causal relationships between cancers and PD have not been fully explored. OBJECTIVE:To study causal relationship between different cancers and PD. METHODS:We used GWAS summary statistics of 15 different types of cancers and two-sample Mendelian randomization to study the causal relationship with PD. RESULTS:There was no evidence to support a causal relationship between the studied cancers and PD. We also performed reverse analyses between PD and cancers with available full summary statistics (melanoma, breast, prostate, endometrial and keratinocyte cancers) and did not find evidence of causal relationship. CONCLUSION:We found no evidence to support a causal relationship between cancers and PD and the previously reported associations could be a result of genetic pleiotropy, shared biology or biases. 10.3233/JPD-202474
Association between Type 1 Diabetes Mellitus and Parkinson's Disease: A Mendelian Randomization Study. Journal of clinical medicine While much evidence suggests that type 2 diabetes mellitus increases the risk of Parkinson's disease (PD), the relationship between type 1 diabetes mellitus (T1DM) and PD is unclear. To study their association, we performed a two-sample Mendelian randomization (MR) using the following statistical methods: inverse variance weighting (IVW), MR-Egger, weight median, and weighted mode. Independent datasets with no sample overlap were retrieved from the IEU GWAS platform. All the MR methods found a lower risk of PD in T1DM (IVW-OR 0.93, 95% CI 0.91-0.96, = 3.12 × 10; MR-Egger-OR 0.93, 95% CI 0.88-0.98, = 1.45 × 10; weighted median-OR 0.93, 95% CI 0.89-0.98, = 2.76 × 10; and weighted mode-OR 0.94, 95% CI 0.9-0.98, = 1.58 × 10). The findings were then replicated with another independent GWAS dataset on T1DM (IVW-OR 0.97, 95% CI 0.95-0.99, = 3.10 × 10; MR-Egger-OR 0.96, 95% CI 0.93-0.99, = 1.08 × 10; weighted median-OR 0.97, 95% CI 0.94-0.99, = 1.88 × 10; weighted mode-OR 0.97, 95% CI 0.94-0.99, = 1.43 × 10). Thus, our study provides evidence that T1DM may have a protective effect on PD risk, though further studies are needed to clarify the underlying mechanisms. 10.3390/jcm13020561
Causal relationships between delirium and Parkinson's disease: a bidirectional two-sample Mendelian randomization study. European journal of medical research BACKGROUND:Previous observational studies have suggested a notably elevated prevalence of delirium in individuals diagnosed with Parkinson's disease (PD), thereby implying a potential increased susceptibility to delirium among PD patients. However, it is imperative to acknowledge that observational studies inherently possess limitations, rendering it arduous to establish a definitive causal or reverse causal association between delirium and PD. METHODS:To explore the relationship between delirium and PD, a bidirectional two-sample Mendelian randomization (MR) was conducted using summary statistics obtained from genome-wide association studies. The main analysis was performed using the inverse-variance weighted (IVW) method, with further analyses conducted using MR Egger, weighted median, and weighted mode to ensure accuracy of findings. Additionally, Cochran's Q statistics and MR Egger intercept were utilized to assess heterogeneity and horizontal pleiotropy, respectively. RESULTS:According to the results obtained from the IVW model, no compelling evidence was found to support a potential causal association between delirium and PD (IVW: odds ratio [OR]: 0.996, 95% confidence interval CI 0.949-1.043, P = 0.845). Additionally, in the reverse direction, based on the results obtained from the IVW model, no significant evidence was found to support a causal association between PD and delirium (IVW: OR: 1.078, 95%CI  0.960-1.204, P = 0.225). A sensitivity analysis verified the reliability of the results. CONCLUSION:According to the MR findings, a bidirectional causal relationship between delirium and PD is not observed. It is crucial to conduct further research in clinical practice to investigate the association between delirium and the risk of PD. 10.1186/s40001-024-01696-9
Heart rate, intelligence in adolescence, and Parkinson's disease later in life. Longinetti Elisa,Zhan Yiqiang,Sata Mizuki,Larsson Henrik,D Onofrio Brian M,Iso Hiroyasu,Wirdefeldt Karin,Fang Fang European journal of epidemiology To investigate whether physical and cognitive fitness measured in late adolescence was associated with future risk of Parkinson's disease (PD). The cohort included 1,259,485 Swedish men with physical fitness, body mass index (BMI), resting heart rate (RHR), blood pressure, intelligence quotient (IQ), and stress resilience measured at the age of 17-20 in relation to conscription. Incident cases of PD were ascertained from the Swedish Patient Register. Hazard ratios were estimated from Cox models, after controlling for multiple confounders. We further performed Mendelian randomization (MR) analyses to assess the causality of the associations, using GWAS summary statistics with > 800,000 individuals. During follow-up, we identified 1,034 cases of PD (mean age at diagnosis = 53). Men with an RHR > 100 beats per minute had a higher risk of PD compared to men with an RHR of 60-100 beats per minute (HR = 1.47; 95% CI = 1.08-1.99). Men with IQ above the highest tertile had a higher risk of PD compared to men with an IQ below the lowest tertile (HR = 1.46; 95% CI = 1.19-1.79). We found no association for physical fitness, BMI, blood pressure, or stress resilience. A causal relationship was suggested by the MR analysis between IQ and PD, but not between RHR and PD. RHR and IQ in late adolescence were associated with a higher risk of PD diagnosed at relatively young age. The association of IQ with PD is likely causal, whereas the association of RHR with PD suggests that altered cardiac autonomic function might start before 20 years of age in PD. 10.1007/s10654-021-00730-y
Visceral adipose tissue had a causal, independent role in lowering the risk of Parkinson's disease: A mendelian randomization study. Liu Yaozhong,Liu Qiming Parkinsonism & related disorders Genetic evidence based on two-sample Mendelian randomization approaches suggested that visceral adipose tissue had a causal, independent role in lowering the risk of Parkinson's disease. Further studies are needed to explore the underlying mechanism. 10.1016/j.parkreldis.2021.10.014
GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease. Brain : a journal of neurology The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied. 10.1093/brain/awac413
Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease. Kia Demis A,Noyce Alastair J,White Jon,Speed Doug,Nicolas Aude, ,Burgess Stephen,Lawlor Debbie A,Davey Smith George,Singleton Andrew,Nalls Mike A,Sofat Reecha,Wood Nicholas W Annals of neurology OBJECTIVE:Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk. METHODS:We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments. RESULTS:We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88-1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively). INTERPRETATION:We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191-199. 10.1002/ana.25294
Physical activities and risk of neurodegenerative diseases: A two-sample Mendelian randomization study. Frontiers in aging neuroscience Objectives:Physical activity (PA) is considered beneficial in slowing the progression and improving the neurodegenerative disease prognosis. However, the association between PA and neurodegenerative diseases remains unknown. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal association between PA phenotypes and neurodegenerative diseases. Materials and methods:Genetic variants robustly associated with PA phenotypes, used as instrumental variables, were extracted from public genome-wide association study (GWAS) summary statistics. Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD), were considered outcomes. GWAS information was also obtained from the most recent large population study of individuals with European ancestry. Multiple MR methods, pleiotropy tests and sensitivity analyses were performed to obtain a robust and valid estimation. Results:We found a positive association between moderate-to-vigorous physical activities and ALS based on the inverse variance weighted MR analysis method (OR: 2.507, 95% CI: 1.218-5.160, = 0.013). The pleiotropy test and sensitivity analysis confirmed the robustness and validity of these MR results. No causal effects of PA phenotypes were found on PD and AD. Conclusion:Our study indicates a causal effect of PA on the risk of neurodegenerative diseases. Genetically predicted increases in self-reported moderate-to-vigorous PA participation could increase the risk of ALS in individuals of European ancestry. Precise and individualized prescriptions of physical activity should be provided to the elderly population. 10.3389/fnagi.2022.991140
Renal function and neurodegenerative diseases : a two-sample Mendelian randomization study. Neurological research BACKGROUND:Observational studies showed renal function had associations with Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and multiple sclerosis (MS). However, it is unknown whether these associations are causal. METHODS:We use a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between renal function and 6 neurodegenerative diseases (NDDs): AD (including familial AD), PD, LBD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and MS. Blood urea nitrogen (BUN), chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) were used to measure renal function. The inverse-variance weighted (IVW) was the predominant estimation method. The results were further validated using sensitivity analysis (i.e. MR Egger regression, Cochran Q statistic of IVW, and leave-one-out method). RESULTS:There was no indication of any causative relationship of BUN, CKD, or eGFR with AD, familial AD, PD, LBD, FTD and ALS (all values >0.05). The IVW analysis demonstrated a causal relationship between eGFR and MS [odds ratio (OR), 4.89; 95% confidence interval (CI), 1.43 to 16.71; P = 0.01] that was not verified in the MR-Egger and weighted median (all values >0.05). However, no causal association of MS with BUN (OR, 0.91; 95% CI, 0.40-2.07; P = 0.82) and CKD (OR,1.04; 95% CI, 0.88-1.23; P = 0.66) was found. There was no single SNP that affects the overall trend. CONCLUSIONS:Our study showed that reduced eGFR was related to MS. The value of this study is that it provides a direction for further research on the relationship between reduced eGFR and MS. 10.1080/01616412.2022.2158640
Mendelian Randomisation Finds No Causal Association between Urate and Parkinson's Disease Progression. Coneys Rachel,Storm Catherine S,Kia Demis A,Almramhi Mona,Wood Nicholas W Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Parkinson's disease (PD) is a common neurodegenerative movement disorder. Observational studies suggest higher levels of plasma urate may protect against Parkinson's risk and progression; however, causality cannot be established. OBJECTIVES:This study set out to determine whether there is a true causal association between urate levels and PD age at onset (AAO) and progression severity using recently released PD AAO and progression genome-wide association study (GWAS) data. METHODS:A large two-sample Mendelian randomization design was employed, using genetic variants underlying urate levels and the latest GWAS data for PD outcomes. RESULTS:This study found no causal association between urate levels and Parkinson's risk, AAO, or progression severity. CONCLUSIONS:Our results predict increasing urate levels as a therapeutic strategy is unlikely to benefit PD patients. © 2021 International Parkinson and Movement Disorder Society. 10.1002/mds.28662
Mapping the human genetic architecture of COVID-19. Nature The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. 10.1038/s41586-021-03767-x
The genetic regulation of protein expression in cerebrospinal fluid. EMBO molecular medicine Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10 , 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome. 10.15252/emmm.202216359
Genetic Variants in Sulfonylurea Targets Affect Parkinson's Disease Risk: A Two-Sample Mendelian Randomization Study. Movement disorders : official journal of the Movement Disorder Society 10.1002/mds.29341
The Effect of Blood Lipids, Type 2 Diabetes, and Body Mass Index on Parkinson's Disease: A Korean Mendelian Randomization Study. Journal of movement disorders OBJECTIVE:Associations between various metabolic conditions and Parkinson's disease (PD) have been previously identified in epidemiological studies. We aimed to investigate the causal effect of lipid levels, type 2 diabetes mellitus (T2DM), and body mass index (BMI) on PD in a Korean population via Mendelian randomization (MR). METHODS:Two-sample MR analyses were performed with inverse-variance weighted (IVW), weighted median, and MR-Egger regression approaches. We identified genetic variants associated with lipid concentrations, T2DM, and BMI in publicly available summary statistics, which were either collected from genome-wide association studies (GWASs) or from meta-analyses of GWAS that targeted only Korean individuals or East Asian individuals, including Korean individuals. The outcome dataset was a GWAS on PD performed in a Korean population. RESULTS:From previous GWASs and meta-analyses, we selected single nucleotide polymorphisms as the instrumental variables. Variants associated with serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, as well as with T2DM and BMI, were selected (n = 11, 19, 17, 89, and 9, respectively). There were no statistically significant causal associations observed between the five exposures and PD using either the IVW, weighted median, or MR-Egger methods (p-values of the IVW method: 0.332, 0.610, 0.634, 0.275, and 0.860, respectively). CONCLUSION:This study does not support a clinically relevant causal effect of lipid levels, T2DM, and BMI on PD risk in a Korean population. 10.14802/jmd.22175
Neuroticism, Smoking, and the Risk of Parkinson's Disease. Sieurin Johanna,Zhan Yiqiang,Pedersen Nancy L,Wirdefeldt Karin Journal of Parkinson's disease BACKGROUND:The relationship among neuroticism, smoking, and Parkinson's disease (PD) is less examined. OBJECTIVE:To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. METHODS:We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. RESULTS:The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). CONCLUSION:These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD. 10.3233/JPD-202522
Investigating the causality of metabolites involved in one-carbon metabolism with the risk and age at onset of Parkinson's disease: A two-sample mendelian randomization study. Zhao Yating,Tian Dandan,Guo Na,Zhang Chenguang,Zhu Ruixia,Liu Xu,Zhang Jian Neurobiology of aging With the aging population and increasing life expectancy, Parkinson's disease (PD), a neurological disorder rapidly increasing in morbidity and mortality, is causing a huge burden on society and the economy. Several studies have suggested that one-carbon metabolites, including homocysteine, vitamin B6, vitamin B12 and folate acid, are associated with PD risk. However, the results remain inconsistent and controversial. Thus, we performed a two-sample Mendelian randomization (MR) study to detect the causality between one-carbon metabolites and PD susceptibility as well as age at PD onset. We collected several genetic variants as instrumental variables from large genome-wide association studies of one-carbon metabolites (homocysteine: N = 14, vitamin B6: N = 1, vitamin B12: N = 10, folate acid: N = 2). We then conducted MR analyses using the inverse variance-weighted (IVW) approach and additional MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to further test causality. The results showed no causal association between circulating homocysteine levels and PD risk (p = 0.868) or age at PD onset (p = 0.222) with the IVW method. Meanwhile, similar results were obtained by three complementary analyses. In addition, we did not observe any evidence that the circulating levels of vitamin B6, vitamin B12 and folate acid affected the risk of PD or age at onset of PD. Our findings implied that lowering homocysteine levels through vitamin B6, vitamin B12 or folate acid supplementation may not be clinically helpful in preventing PD or delaying the age at PD onset. 10.1016/j.neurobiolaging.2021.06.023
Genetic mechanisms of critical illness in COVID-19. Nature Host-mediated lung inflammation is present, and drives mortality, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. 10.1038/s41586-020-03065-y
Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Type 2 diabetes (T2DM) and Parkinson's disease (PD) are prevalent diseases that affect an aging population. Previous systematic reviews and meta-analyses have explored the relationship between diabetes and the risk of PD, but the results have been conflicting. OBJECTIVE:The objective was to investigate T2DM as a determinant of PD through a meta-analysis of observational and genetic summary data. METHODS:A systematic review and meta-analysis of observational studies was undertaken by searching 6 databases. We selected the highest-quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate the causal effects of genetic liability toward T2DM on PD risk and progression, using summary data derived from genome-wide association studies. RESULTS:In the observational part of the study, pooled effect estimates showed that T2DM was associated with an increased risk of PD (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (standardized mean difference [SMD] 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD -0.92, 95% CI -1.50 to -0.34). Using MR, we found supportive evidence for a causal effect of diabetes on PD risk (inverse-variance weighted method [IVW] OR 1.08, 95% CI 1.02-1.14; P = 0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; P = 0.032) but not on cognitive progression. CONCLUSIONS:Using meta-analyses of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk and new evidence to support a role in PD progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.28551
Effect of plasma vitamin C levels on Parkinson's disease and age at onset: a Mendelian randomization study. Liu Haijie,Zhang Yan,Zhang Haihua,Wang Longcai,Wang Tao,Han Zhifa,Wu Liyong,Liu Guiyou Journal of translational medicine BACKGROUND:Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson's disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. METHODS:We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. RESULTS:We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = - 1.134, 95% CI: [- 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = - 1.750, 95% CI: [- 3.396, - 0.105], P = 0.037) and MR-Egger (beta = - 2.592, 95% CI: [- 4.623, - 0.560], P = 0.012). CONCLUSIONS:We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD. 10.1186/s12967-021-02892-5
Bidirectional relationship between olfaction and Parkinson's disease. medRxiv : the preprint server for health sciences Background:Hyposmia (loss of smell) is a common early symptom of Parkinson's disease (PD). The shared genetic architecture between hyposmia and PD is unknown. Methods:We leveraged genome-wide association study (GWAS) results for self-assessment of 'ability to smell' and PD diagnosis. Linkage disequilibrium score regression (LDSC) and Local Analysis of [co]Variant Association (LAVA) were used to identify genome-wide and local genetic correlations. Mendelian randomization was used to identify potential causal relationships. Results:LDSC found that sense of smell negatively correlated at a genome-wide level with PD. LAVA found negative correlations in four genetic loci near , , , and . Using Mendelian randomization we found evidence for strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. Conclusions:Hyposmia and PD share genetic liability in only a subset of the major PD risk genes. While there was definitive evidence that PD can lower the sense of smell, there was only suggestive evidence for the reverse. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia. 10.1101/2023.10.18.23297218
The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. OBJECTIVE:To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. METHODS:We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. RESULTS:At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. CONCLUSIONS:Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.29133
Plasma urate and risk of Parkinson's disease: A mendelian randomization study. Kobylecki Camilla J,Nordestgaard Børge G,Afzal Shoaib Annals of neurology OBJECTIVE:Urate is a potent antioxidant, and high plasma urate has been associated with lower incidence of Parkinson's disease (PD) in epidemiological studies. We tested the hypothesis that high concentrations of plasma urate are associated with low incidence of PD. METHODS:We performed observational and genetic analyses using plasma urate and the urate SLC2A9 rs7442295 and ABCG2 rs2231142 genotype in >102,000 individuals from the CGPS (Copenhagen General Population Study). Information on PD and mortality was from national patient and death registries. Incidences of PD were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses. RESULTS:In total, 398 individuals were diagnosed with PD, of which 285 were incident cases. The multivariable adjusted hazard ratio for PD was 0.56 (95% confidence interval [CI], 0.41-0.77) for the highest versus the lowest tertile of plasma urate (p for trend across 3 groups, 8 × 10 ). Each one-allele increase in the combined allele score was associated with 19μmol/l (95% CI, 18.5-19.9) higher plasma urate. In observational analyses, a 50μmol/l higher plasma urate was associated with a hazard ratio of 0.85 (0.77-0.92) for PD; in instrumental variable analyses, 50μmol/l higher plasma urate was associated with an odds ratio of 1.20 (0.85-1.71) for PD. INTERPRETATION:High plasma urate was associated with lower risk of PD in observational analyses; however, in instrumental variable analysis, high plasma urate was not associated with low risk of PD. Thus, our data do not support a causal relationship between high plasma urate and low risk of PD. Ann Neurol 2018;84:178-190. 10.1002/ana.25292
Genetic predisposition to Parkinson's disease and risk of cardio and cerebrovascular disease: a Mendelian randomization study. Parkinsonism & related disorders BACKGROUND:Observational studies suggest that Parkinson's disease (PD) is related with the risk of cardio and cerebrovascular disease. However, the causality is not yet fully established. Therefore, we employed Mendelian randomization to assess whether PD is related to risk of ischemic stroke (IS), IS subtypes, coronary artery disease (CAD) and myocardial infarction (MI). METHODS:Eighty-eight and eleven single nucleotide polymorphisms associated with PD at the genome-wide significance level, were used as instrumental variables for PD in European and East Asian population respectively. Using a 2-sample MR, we examined associations with IS, IS related subtypes, CAD and MI in European population. We also assessed the causal association of PD with IS and CAD in East Asian population. The primary MR analyses were performed by using the random-effects inverse variance weighted approach. RESULTS:In European population, genetic predisposition to PD was related to higher risk of IS (odds ratio [OR], 1.03 per doubling in odds of PD; 95% confidence interval [CI], 1.01-1.05; P = 0.002) and cardioembolic stroke (OR, 1.08 per doubling in odds of PD; 95% CI, 1.04-1.12; P = 1.29 × 10), but not large artery stroke, small vessel stroke, CAD and MI. In East Asian population, we found no evidence of causal effect of PD on the risk of IS and CAD. CONCLUSIONS:This study found that genetic predisposition to PD is related to higher risk of IS and cardioembolic stroke in European population. 10.1016/j.parkreldis.2021.11.021
Mendelian Randomization - the Key to Understanding Aspects of Parkinson's Disease Causation? Noyce Alastair J,Nalls Mike A Movement disorders : official journal of the Movement Disorder Society Parkinson's disease has multiple determinants and is associated with a wide range of exposures that appear to modify risk in traditional observational studies, including numerous lifestyle and environmental factors. Across other fields of medicine, Mendelian randomization has emerged as a powerful method to examine whether associations between exposures and disease outcomes are causal. Here we discuss the concept of Mendelian randomization, its potential relevance to Parkinson's disease, and suggest avenues through which the method could be employed to further understanding of the causal basis of Parkinson's disease. 10.1002/mds.26492
The Parkinson's Disease Mendelian Randomization Research Portal. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE:To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS:We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS:We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS:We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.27873
Understanding the effect of smoking and drinking behavior on Parkinson's disease risk: a Mendelian randomization study. Scientific reports Previous observational studies have identified correlations between Parkinson's disease (PD) risk and lifestyle factors. However, whether or not those associations are causal remains unclear. To infer causality between PD risk and smoking or alcohol intake, we conducted a two-sample Mendelian randomization study using genome-wide association study summary statistics from the GWAS & Sequencing Consortium of Alcohol and Nicotine use study (1.2 million participants) and the latest meta-analysis from the International Parkinson's Disease Genomics Consortium (37,688 PD cases and 18,618 proxy-cases). We performed sensitivity analyses, including testing for pleiotropy with MR-Egger and MR-PRESSO, and multivariable MR modeling to account for the genetic effects of competing substance use traits on PD risk. Our results revealed causal associations of alcohol intake (OR 0.79; 95% CI 0.65-0.96; p = 0.021) and smoking continuation (which compares current vs. former smokers) (OR 0.64; 95% CI 0.46-0.89; p = 0.008) with lower PD risk. Multivariable MR analyses showed that the causal association between drinks per week and PD is unlikely due to confounding by smoking behavior. Finally, frailty analyses suggested that the causal effects of both alcohol intake and smoking continuation on PD risk estimated from MR analysis are not explained by the presence of survival bias alone. Our findings support the role of smoking as a protective factor against PD, but only when comparing current vs. former smokers. Similarly, increased alcohol intake had a protective effect over PD risk, with the alcohol dehydrogenase 1B (ADH1B) locus as a potential candidate for further investigation of the mechanisms underlying this association. 10.1038/s41598-021-93105-y
Sleep, Pain, and Neurodegeneration: A Mendelian Randomization Study. Frontiers in neurology Our aim was to determine whether the genetic liability to sleep and pain-related traits have a causal effect on risk of neurodegeneration in individuals of predominantly European ancestry. We selected five neurodegenerative disorders, namely, age-related macular degeneration (AMD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Parkinson's disease (PD). Sleep duration (SD), short sleep (SS), long sleep (LS), chronotype (CHR), morning person (MP), insomnia (INS), and multisite chronic pain (MCP) were considered as exposures. We conducted Mendelian randomization (MR) using an inverse-variance weighted (IVW) method to compute causal effect estimates using latest available GWAS data sets. The MP phenotype was observed as the strongest risk factor for genetic liability to AMD (OR = 1.192; 95% CI 1.078, 1.318, = 0.0007). We observed suggestive evidence of risky effects of CHR on AMD ( = 0.0034), SS on AD ( = 0.0044), and INS on ALS ( = 0.0123). However, we failed to observe any role of pain. The results were robust on sensitivity analyses. Our study highlighted the role of MP as a risk factor for AMD. 10.3389/fneur.2022.765321
The Promise of Mendelian Randomization in Parkinson's Disease: Has the Smoke Cleared Yet for Smoking and Parkinson's Disease Risk? Journal of Parkinson's disease This commentary discusses the strengths and limitations of utilizing the Mendelian randomization (MR) approach in Parkinson's disease (PD) studies. Epidemiologists proposed to employ MR when genetic instruments are available that represent reliable proxies for modifiable lifelong exposures which elude easy measurement in studies of late onset diseases like PD. Here, we are using smoking as an example. The great promise of the MR approach is its resilience to confounding and reverse causation. Nevertheless, the approach has some drawbacks such as being liable to selection- and survival-bias, it makes some strong assumptions about the genetic instruments employed, and requires very large sample sizes. When interpreted carefully and put into the context of other studies that take both genetics and the environment into consideration, MR studies help us to not only ask interesting questions but also can support causal inference and provide novel insights. 10.3233/JPD-223188
Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis. Wingo Aliza P,Liu Yue,Gerasimov Ekaterina S,Gockley Jake,Logsdon Benjamin A,Duong Duc M,Dammer Eric B,Robins Chloe,Beach Thomas G,Reiman Eric M,Epstein Michael P,De Jager Philip L,Lah James J,Bennett David A,Seyfried Nicholas T,Levey Allan I,Wingo Thomas S Nature genetics Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD), but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies. 10.1038/s41588-020-00773-z
Neurodegenerative disease and antioxidant biomarkers: A bidirectional Mendelian randomization study. Frontiers in neurology Objective:Previous observational studies have suggested that antioxidant imbalance is correlated with neurodegenerative diseases, while its cause-effect remains unclear. Thus, the goal of the present study is to explore the causal relationship between 11 antioxidant biomarkers and 3 most common neurodegenerative diseases [Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD)]. Methods:A bidirectional Mendelian randomization (MR) study was performed to investigate the causal effects by using 3 main methods (Variance Weighted (IVW), Weighted Median (WM), and MR-Egger regression) in the European population. The data of 11 antioxidant biomarkers were obtained from the open database by the most up-to-date Genome-Wide Association Studies (GWAS), the summary statistics of PD and ALS were obtained from the International Parkinson's Disease Genomics Consortium (IPDGC) (33,674 cases, and 449,056 controls), and the International Amyotrophic Lateral Sclerosis Genomics Consortium (IALSC) (20,806 cases and 59,804 controls), respectively. For AD, we specifically used two recently published GWAS data, one from the International Genomics of Alzheimer's Project (IGAP) (21,982 cases and 41,944 controls), and the other from a large meta-analysis (71,880 cases and 383,378 controls) as validation data. Results:Based on the Bonferroni correction  < 0.0015, there was no significant causal evidence for the antioxidant biomarkers on neurodegenerative diseases, however, the reverse analysis found that AD was significantly related to the decrease in retinol (IVW: beta = -0.023,  = 0.0007; WM: beta = -0.025,  = 0.0121), while the same analysis was carried out between the AD validation database and retinol, the results were consistent (IVW: beta = -0.064,  = 0.025). Moreover, AD on Glutathione S-transferase (GST), PD on Glutathione Peroxidase (GPX) as well as PD on uric acid (UA) also indicated potential causal-and-effect associations (IVW:  = 0.025;  = 0.027;  = 0.021, respectively). Conclusions:There was no sufficient evidence that antioxidant imbalance has a significant causal effect on neurodegenerative diseases. However, this study revealed that genetically predicted AD was significantly related to the decrease in retinol, which provides a new insight into previous research and indicates the possibility to regard retinol as potential biomarker for the diagnosis and progress of AD. 10.3389/fneur.2023.1158366
Effects of ulcerative colitis and Crohn's disease on neurodegenerative diseases: A Mendelian randomization study. Frontiers in genetics Both ulcerative colitis (UC) and Crohn's disease (CD) are associated with neurodegenerative diseases (NDs) in observational studies, but the causality remains controversial. We aimed to use Mendelian randomization (MR) analysis to explore causal associations between UC and CD and NDs. We used single nucleotide polymorphisms (SNPs) associated ( < 5 × 10) with UC and CD as instrumental variables (IVs) to perform the MR analysis on the risks of three NDs, namely, Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS). The inverse variance weighted (IVW) was the primary method and supplement with the weighted median and MR-Egger regression. Moreover, the MR-Egger intercept test, Cochran's Q test, and "leave one out" sensitivity analysis were implemented to assess the horizontal pleiotropy, heterogeneities, and stability of these SNPs on NDs. To verify the stability of the results, we re-run the MR analysis by using another set of IVs of UC and CD. A reverse causality analysis was conducted to test whether NDs were causally associated with UC or CD. The significance threshold was set at < 0.05/6 = 0.008. In the primary MR analysis, the IVW method yielded no evidence to support a causal association between UC and PD (: 1.01, 95% : 0.96-1.06, = 0.65), AD (: 1.00, 95% : 0.99-1.00, = 0.57), or ALS (: 0.98, 95% : 0.96-1.01, = 0.24), and neither did the MR-Egger and weighted median methods. Our MR analysis also suggested no definitively causal effect of the genetically predicted CD on PD (: 1.01, 95% : 0.97-1.05, = 0.54), AD (: 1.00, 95% : 0.99-1.00, = 0.26), or ALS (: 0.99, 95% : 0.96-1.02, = 0.41), as well as MR-Egger and weighted median methods. Consistent results were found in validation analyses. We did not find a significant causal effect of NDs on UC or CD in the reverse MR analysis. No evidence indicated an association between the risks of NDs and genetically predicted UC or CD. The MR results did not support a causal association between UC or CD and three NDs. 10.3389/fgene.2022.846005
No causal relationship between thyroid function and Parkinson's disease: A bidirectional Mendelian randomization study. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology BACKGROUND:Parkinson's disease (PD) is the second most prevalent degenerative disease globally. While observational studies have demonstrated a correlation between thyroid function and PD, the causal relationship between these two factors remains uncertain. METHODS:A bidirectional Mendelian randomization (MR) analysis was performed to explore the causal relationship between thyroid function (free thyroxine [FT4], thyroid-stimulating hormone [TSH], hyperthyroidism, and hypothyroidism) and PD. GWAS summary-level statistics of thyroid function and PD were obtained from publicly available GWAS databases. The inverse variance weighted method was the main MR approach to assess causal associations. In addition, two additional MR methods (MR-Egger regression and weighted median) were performed to supplement the IVW. Furthermore, various sensitivity tests were performed to verify the reliability of the MR findings: (i) Heterogeneity was examined by Cochrane's Q test. (ii) Horizontal pleiotropy was assessed by the MR-Egger intercept test and MR-PRESSO global test. (iii) The robustness of MR results was estimated using the leave-one-out method. RESULTS:Various MR results showed that FT4, TSH, hyperthyroidism, and hypothyroidism did not causally affect PD (P > 0.05). Likewise, PD did not causally affect FT4, TSH, hyperthyroidism, and hypothyroidism (P > 0.05). Cochrane's Q test indicated that MR analysis was not affected by significant heterogeneity (P > 0.05). MR-Egger intercept test and MR-PRESSO global test indicated that MR analysis was not affected by a remarkable horizontal pleiotropy (P > 0.05). The leave-one-out method demonstrated the stability of MR results. CONCLUSION:MR analysis did not support a causal relationship between thyroid function and PD. 10.1007/s10072-023-07176-y
Inflammation and Brain Structure in Alzheimer's Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study. Molecular neurobiology Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = -9.088, p-value = 1.02 × 10; sTREM2: z-score = -7.495, p-value = 6.61 × 10). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = -4.238, p-value = 2.26 × 10) and pole temporal (z-score = -4.549, p-value = 5.40 × 10). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD. 10.1007/s12035-023-03648-6
Exploring the association between air pollution and Parkinson's disease or Alzheimer's disease: a Mendelian randomization study. Environmental science and pollution research international The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM, PM, NO, and NO exposure and the occurrence of Parkinson's disease (PD) and Alzheimer's disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10) with PM, PM, NO, and NO. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO and PM exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms. 10.1007/s11356-023-31047-w
Causal effect of gut-microbiota-derived metabolite trimethylamine N-oxide on Parkinson's disease: A Mendelian randomization study. European journal of neurology BACKGROUND AND PURPOSE:It has been suggested that trimethylamine N-oxide (TMAO) is related to Parkinson's disease (PD) in observational studies. However, the direction of this association is inconsistent. An exploratory Mendelian randomization study was conducted to investigate whether TMAO and its precursors have a causal relationship with PD. METHODS:Summary statistics were obtained for single nucleotide polymorphisms related to circulating levels of TMAO, betaine, carnitine and choline, and the corresponding data for the risk, age at onset and progression of PD from genome-wide association studies. Inverse-variance weighting was used as the primary method for effect estimation. The false discovery rate was applied to the correction of multiple testing. A p value of association <0.05 but above the false discovery rate corrected threshold was deemed suggestive evidence of a possible association. A range of robust Mendelian randomization methods were used for sensitivity analysis. RESULTS:Suggestive evidence was observed of an inverse causal effect of TMAO on motor fluctuations (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.731, 0.990, p = 0.037) and carnitine on insomnia (OR 0.817, 95% CI 0.700, 0.954, p = 0.010) and a positive causal effect of betaine on Hoehn-Yahr stage (OR 1.397, 95% CI 1.112, 1.756, p = 0.004), Unified Parkinson's Disease Rating Scale (UPDRS) III score (β = 0.138, 95% CI 0.051, 0.225, p = 0.002), motor fluctuations (OR 1.236, 95% CI 1.011, 1.511, p = 0.039), and choline on UPDRS IV (β = 0.106, 95% CI 0.026, 0.185, p = 0.009) and modified Schwab and England Activities of Daily Living Scale score (β = 0.806, 95% CI 0.127, 1.484, p = 0.020). CONCLUSIONS:Our findings provide suggestive evidence that TMAO and its precursors have a causal effect on the progression of PD. Further investigation of the underlying mechanisms is required. 10.1111/ene.15702
Associations between polyunsaturated fatty acid concentrations and Parkinson's disease: A two-sample Mendelian randomization study. Frontiers in aging neuroscience Introduction:Observational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized control trials showed possible improvement in PD symptoms with PUFA supplement but had small study population and limited intervention time. Methods:A two-sample Mendelian randomization was designed to evaluate the causal relevance between PUFAs and PD, using genetic variants of PUFAs as instrumental variables and PD data from the largest genome-wide association study as outcome. Inverse variance weighted (IVW) method was applied to obtain the primary outcome. Mendelian randomization Egger regression, weighted median and weighted mode methods were exploited to assist result analyses. Strict Mendelian randomization and multivariable Mendelian randomization (MVMR) were used to estimate direct effects of PUFAs on PD, eliminating pleiotropic effect. Debiased inverse variance weighted estimator was implemented when weak instrument bias was introduced into the analysis. A variety of sensitivity analyses were utilized to assess validity of the results. Results:Our study included 33,674 PD cases and 449,056 controls. Higher plasma level of arachidonic acid (AA) was associated with a 3% increase of PD risk per 1-standard deviation (SD) increase of AA (IVW; Odds ratio (OR)=1.03 [95% confidence interval (CI) 1.01-1.04],  = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04],  =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05],  =5.88E-04), result was still significant. Increased level of eicosapentaenoic acid (EPA) showed possible relevance with increased PD risk after adjustment of pleiotropy (MVMR; OR=1.05 [95% CI 1.01-1.08],  =5.40E-03). Linoleic acid (LA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were found not causally relevant to PD risk. Various sensitivity analyses verified the validity of our results. In conclusion, our findings from Mendelian randomization suggested that elevated levels of AA and possibly EPA might be linked to a higher risk of PD. No association between PD risk and LA, DHA, DPA, or ALA was found. Discussion:The odds ratio for plasma AA and PD risk was weak. It is important to approach our results with caution in clinical practice and to conduct additional studies on the relationship between PUFAs and PD risk. 10.3389/fnagi.2023.1123239
Fibrinogen in Alzheimer's Disease, Parkinson's Disease and Lewy Body Dementia: A Mendelian Randomization Study. Frontiers in aging neuroscience Fibrinogen is reportedly associated with neurodegenerative diseases (NDs), but the underlying causality remains controversial. Using Mendelian randomization (MR), this study aimed to assess the causal association between fibrinogen and Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Genetic variants associated with fibrinogen and γ-fibrinogen were selected and used as instrumental variables. The effect estimates of the main analysis were obtained by inverse-variance weighting (IVW), complemented by sensitivity analyses to verify model assumptions, and multivariable MR was conducted to control for potential pleiotropic effect. Two-step MR was performed to assess the causal association through mediators. The main analysis suggested no causal association between genetically predicted plasma fibrinogen and γ-fibrinogen levels and the risk of AD, PD, and LBD. The effect estimates did not change in the follow-up sensitivity analyses and MVMR. However, the two-step MR analysis provides evidence that fibrinogen may contribute to the risk of AD via CRP levels. There was an inverse effect of adult height levels on the risk of AD. Our results support the effects of fibrinogen on the risk of AD through increasing plasma CRP levels. Our study found no evidence to support the effects of genetically determined fibrinogen and γ-fibrinogen levels on the risk of PD and LBD. Additionally, our findings suggested an inverse association between genetically determined adult height levels and the risk of AD. Future studies are needed to elucidate the underlying mechanisms and their clinical applications. 10.3389/fnagi.2022.847583
Genetically Predicted Levels of Circulating Inflammatory Cytokines and the Risk and Age at Onset of Parkinson's Disease: A Two-Sample Mendelian Randomization Study. Zhao Yating,Zhang Xiaoqian,Guo Na,Tian Dandan,Zhang Chenguang,Mu Changqing,Han Chen,Zhu Ruixia,Zhang Jian,Liu Xu Frontiers in aging neuroscience Parkinson's disease (PD) is widely considered to be a disabling neurodegenerative disorder, which has been ranked second worldwide just after Alzheimer's disease. Until present, a wide range of studies has focused on the role of circulating inflammatory cytokines in the development of PD. However, the causal relationship between circulating inflammatory cytokines and the risk and age at the onset of PD has not been elucidated. Hence, to evaluate the effects of circulating inflammatory cytokines on the risk or age at the onset of PD more accurately, we conducted this two-sample Mendelian randomization (MR) study involving summary statistics from genome-wide association studies (GWASs). Totally, we included a GWAS for inflammatory cytokines (8,293 participants), a meta-analysis of GWASs for PD risk (482,730 participants), and a GWAS dataset for age at the onset of PD (17,996 patients with PD). A total of 149 and 131 polymorphisms for exploring relationships between 19 inflammatory cytokines and the risk and age at the onset of PD were obtained as instrumental variants. Then, we used a total of five MR methods, including inverse-variance weighted (IVW), Wald ratio, MR Egger regression, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Finally, we found a causal association between circulating levels of macrophage inflammatory protein-1 beta (MIP1b) and PD risk in the IVW method (OR: 1.06; 95% CI: 1.02-1.10; = 0.001). Meanwhile, other MR estimates by weighted median and MR-PRESSO methods yielded similar effect estimates. Besides, we identified a suggestive association of interleukin-16 (IL-16) levels with PD risk (OR: 1.08; 95% CI: 1.00-1.17; = 0.037). For age at PD onset, there was no evidence supporting its correlation with inflammatory cytokines. Our findings implied that MIP1b and IL-16 may be novel biomarkers and promising therapeutic targets for PD development. 10.3389/fnagi.2022.811059
Assessment of causal effects of physical activity on neurodegenerative diseases: A Mendelian randomization study. Wu Peng-Fei,Lu Hui,Zhou Xiaoting,Liang Xuchen,Li Ruizhuo,Zhang Wan,Li Danyang,Xia Kun Journal of sport and health science BACKGROUND:Physical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation. METHODS:We performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria). RESULTS:Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88-2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32-8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01-1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88-0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29-0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91-1.02, p = 0.22). CONCLUSION:Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS. 10.1016/j.jshs.2021.01.008
Shared Genetic Background between Parkinson's Disease and Schizophrenia: A Two-Sample Mendelian Randomization Study. Brain sciences : Parkinson's disease (PD) and schizophrenia often share symptomatology. Psychotic symptoms are prevalent in patients with PD, and similar motor symptoms with extrapyramidal signs are frequently observed in antipsychotic-naïve patients with schizophrenia as well as premorbid families. However, few studies have examined the relationship between PD and schizophrenia. We performed this study to evaluate whether genetic variants which increase PD risk influence the risk of developing schizophrenia, and vice versa. : Two-sample Mendelian randomization (TSMR) with summary statistics from large-scale genome-wide association studies (GWAS) was applied. Summary statistics were extracted for these instruments from GWAS of PD and schizophrenia; : We found an increase in the risk of schizophrenia per one-standard deviation (SD) increase in the genetically-predicted PD risk (inverse-variance weighted method, odds ratio = 1.10; 95% confidence interval, 1.05-1.15; = 3.49 × 10). The association was consistent in sensitivity analyses, including multiple TSMR methods, analysis after removing outlier variants with potential pleiotropic effects, and analysis after applying multiple GWAS subthresholds. No relationships were evident between PD and smoking or other psychiatric disorders, including attention deficit hyperactivity disorder, autism spectrum disorder, bipolar affective disorder, major depressive disorder, Alzheimer's disease, or alcohol dependence. However, we did not find a reverse relationship; genetic variants increasing schizophrenia risk did not alter the risk of PD; : Overall, our findings suggest that increased genetic risk of PD can be associated with increased risk of schizophrenia. This association supports the intrinsic nature of the psychotic symptom in PD rather than medication or environmental effects. Future studies for possible comorbidities and shared genetic structure between the two diseases are warranted. 10.3390/brainsci11081042
Obstructive sleep apnea and the risk of Alzheimer's disease and Parkinson disease: A Mendelian randomization study OSA, Alzheimer's disease and Parkinson disease. Sleep medicine BACKGROUND:Previous studies reported that obstructive sleep apnea (OSA) was associated with neurodegenerative diseases. However, whether these associations are causal are still unsettled. In our study, we investigated the causal effects of genetically-predicted OSA on Alzheimer's disease (AD) and Parkinson disease (PD). METHODS:We implemented two-sample Mendelian randomization to judge causation using summary statistics from three independent and large genome-wide association studies on OSA (cases n = 16,761, controls n = 201,194), AD (cases n = 71,880, controls n = 383,378) and PD (cases n = 33,774, controls n = 449,056). Four single nucleotide polymorphisms (SNPs) with genome-wide significance associated with OSA served as instrumental variables. We prioritized the inverse variance weighted method when generating unconfounded estimates. Besides, MR-Egger regression, weighted mode, and weighted median methods were adopted as a supplement to the inverse variance weighted method. RESULTS:We found no evidence supporting significant causal relationships between OSA and AD or PD among European population. The risk ratio of AD was 0.99 (95% confidence interval (CI) [0.92,1.08]) and that of PD was 0.82 (95%CI [0.47, 1.40]). Results from alternative approaches were generally consistent with that of the inverse variance weighted method. CONCLUSION:The present study found no evidence for causal associations between OSA and the risk of AD or PD in individuals of European ancestry. 10.1016/j.sleep.2022.06.004
Mendelian Randomization Analysis Reveals No Causal Relationship Between Plasma α-Synuclein and Parkinson's Disease. Molecular neurobiology So far, the studies exploring plasma α-synuclein as a biomarker of Parkinson's disease (PD) have provided contradictory results. Here, we first employed the Mendelian randomization (MR) approach to elucidate their potential causal relationship. Five genetic instrumental variables of plasma α-synuclein were acquired from two publicly available datasets. Three independent genome-wide association studies of PD were used as outcome cohorts (PD cohorts 1, 2, and 3). Two-sample MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and leave-one-out methods. Though the IVW approach demonstrated positive plasma α-synuclein effect on the PD risk in three outcome cohorts (OR = 1.134, 1.164, and 1.189, respectively), the P values were all larger than 0.05. The conclusions were robust under complementary sensitivity analyses. Our results did not support the causal relationship between plasma α-synuclein and PD. 10.1007/s12035-023-03206-0
Expanding causal genes for Parkinson's disease via multi-omics analysis. NPJ Parkinson's disease Genome‑wide association studies (GWASs) have revealed numerous loci associated with Parkinson's disease (PD). However, some potential causal/risk genes were still not revealed and no etiological therapies are available. To find potential causal genes and explore genetically supported drug targets for PD is urgent. By integrating the expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood, cerebrospinal fluid (CSF) and brain) and PD GWAS summary statistics, a pipeline combing Mendelian randomization (MR), Steiger filtering analysis, Bayesian colocalization, fine mapping, Protein-protein network and enrichment analysis were applied to identify potential causal genes for PD. As a result, GPNMB displayed a robust causal role for PD at the protein level in the blood, CSF and brain, and transcriptional level in the brain, while the protective role of CD38 (in brain pQTL and eQTL) was also identified. We also found inconsistent roles of DGKQ on PD between protein and mRNA levels. Another 9 proteins (CTSB, ARSA, SEC23IP, CD84, ENTPD1, FCGR2B, BAG3, SNCA, FCGR2A) were associated with the risk for PD based on only a single pQTL after multiple corrections. We also identified some proteins' interactions with known PD causative genes and therapeutic targets. In conclusion, this study suggested GPNMB, CD38, and DGKQ may act in the pathogenesis of PD, but whether the other proteins involved in PD needs more evidence. These findings would help to uncover the genes underlying PD and prioritize targets for future therapeutic interventions. 10.1038/s41531-023-00591-0
Mendelian randomization analysis does not reveal a causal influence of mental diseases on osteoporosis. Frontiers in endocrinology Introduction:Osteoporosis (OP) is primarily diagnosed through bone mineral density (BMD) measurements, and it often leads to fracture. Observational studies suggest that several mental diseases (MDs) may be linked to OP, but the causal direction of these associations remain unclear. This study aims to explore the potential causal association between five MDs (Schizophrenia, Depression, Alzheimer's disease, Parkinson's disease, and Epilepsy) and the risk of OP. Methods:First, single-nucleotide polymorphisms (SNPs) were filtered from summary-level genome-wide association studies using quality control measures. Subsequently, we employed two-sample Mendelian randomization (MR) analysis to indirectly analyze the causal effect of MDs on the risk of OP through bone mineral density (in total body, femoral neck, lumbar spine, forearm, and heel) and fractures (in leg, arm, heel, spine, and osteoporotic fractures). Lastly, the causal effect of the MDs on the risk of OP was evaluated directly through OP. MR analysis was performed using several methods, including inverse variance weighting (IVW)-random effects, IVW-fixed effects, maximum likelihood, weighted median, MR-Egger regression, and penalized weighted median. Results:The results did not show any evidence of a causal relationship between MDs and the risk of OP (with almost all P values > 0.05). The robustness of the above results was proved to be good. Discussion:In conclusion, this study did not find evidence supporting the claim that MDs have a definitive impact on the risk of OP, which contradicts many existing observational reports. Further studies are needed to determine the potential mechanisms of the associations observed in observational studies. 10.3389/fendo.2023.1125427
Evaluation of causality between ADHD and Parkinson's disease: Mendelian randomization study. Li Gloria Hoi-Yee,Ge Grace Mengqin,Cheung Ching-Lung,Ip Patrick,Coghill David,Wong Ian Chi-Kei European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology In a retrospective cohort study, patients with attention-deficit hyperactivity disorder (ADHD) and psychostimulant prescription were associated with increased risk of Parkinson's disease (PD). It is unclear whether ADHD per se or psychostimulant prescription is associated with PD. We aim to determine if genetic correlation or/and causal association exists between ADHD and PD using summary statistics obtained from the largest meta-analysis of genome-wide association studies of ADHD (20,183 cases; 35,191 controls) and PD (26,421 cases; 442,271 controls). Genetic correlation was tested between ADHD and PD by linkage disequilibrium score regression. Causal estimate was assessed by inverse-variance weighted (IVW) method as the main mendelian randomization analysis, with sensitivity analyses to detect horizontal pleiotropy. Weak and inverse genetic correlation existed between ADHD and PD (r=-0.100;SE=0.045;P = 0.026). Univariable IVW analysis with 10 and 77 genetic instruments respectively revealed null association for ADHD with PD (OR=0.930 per doubling in odds of ADHD; 95% CI:0.792-1.092) and PD with ADHD (OR=0.986 per doubling in odds of PD; 95% CI:0.956-1.015). Multivariable IVW analyses adjusted for BMI/smoking also revealed null association of ADHD with PD. Using 58 PD-associated genetic instruments, multivariable IVW analysis with/without adjustment for BMI/smoking suggested a weak and inverse causal association for PD on ADHD, but cautious interpretation is required. This well-powered study did not support causality between ADHD and PD. The observed positive association between ADHD and PD is more likely to be caused by unmeasured confounders. As psychostimulant use is associated with high risk of early-onset PD, future research should focus on this area. 10.1016/j.euroneuro.2020.06.001
Mendelian Randomization Studies: A Path to Better Understand Sex and Gender Differences in Parkinson's Disease? Gan-Or Ziv,Wood Nicholas W Movement disorders : official journal of the Movement Disorder Society 10.1002/mds.28765
Lack of Causal Associations of Inflammatory Bowel Disease with Parkinson's Disease and Other Neurodegenerative Disorders. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Observational studies have indicated associations between inflammatory bowel disease (IBD) and neurodegenerative diseases, including Parkinson's disease (PD). OBJECTIVE:To evaluate the causal associations of IBD with PD and other selected neurodegenerative disorders using updated data. METHODS:Bidirectional two-sample Mendelian randomization studies using genome-wide association studies summary statistics of IBD and PD. RESULTS:We found a lack of evidence for the causal association of IBD on PD (odds ratio [OR], 1.014; 95% confidence interval [CI], 0.967-1.063; P = 0.573). Reverse analysis also indicated no evidence of a causal effect for PD on IBD (OR, 0.978; 95% CI, 0.910-1.052; P = 0.549). The causality between IBD and Alzheimer's disease, amyotrophic lateral sclerosis, and multiple sclerosis was unfounded (all P > 0.05). CONCLUSIONS:The updated analyses provide no clear evidence for causal associations of IBD with PD or the other three neurodegenerative diseases. Potential confounders might contribute to the previously observed associations, and further investigations are warranted. © 2023 International Parkinson and Movement Disorder Society. 10.1002/mds.29386
CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study. Journal of neuroinflammation BACKGROUND:Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been described as a biomarker for microglial activation, which were observed increased in a variety of neurological disorders. OBJECTIVE:Our objective was to explore whether genetically determined CSF sTREM2 levels are causally associated with different neurological diseases by conducting a two-sample Mendelian randomization (MR) study. METHODS:Single nucleotide polymorphisms significantly associated with CSF sTREM2 levels were selected as instrumental variables to estimate the causal effects on clinically common neurological diseases, including stroke, Alzheimer's diseases, Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy and their subtypes. Summary-level statistics of both exposure and outcomes were applied in an MR framework. RESULTS:Genetically predicted per 1 pg/dL increase of CSF sTREM2 levels was associated with higher risk of multiple sclerosis (OR = 1.038, 95%CI = 1.014-1.064, p = 0.002). Null association was found in risk of other included neurological disorders. CONCLUSIONS:These findings provide support for a potential causal relationship between elevated CSF sTREM2 levels and higher risk of multiple sclerosis. 10.1186/s12974-022-02443-9
Mendelian randomization reveals association between retinal thickness and non-motor symptoms of Parkinson's disease. NPJ Parkinson's disease Retinal thickness is related to Parkinson's disease (PD), but its association with the severity of PD is still unclear. We conducted a Mendelian randomized (MR) study to explore the association between retinal thickness and PD. For the two-sample MR analysis, the summary statistics obtained from genome-wide association studies on the thickness of Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) were employed as exposure, while the summary statistics associated with PD were used as the outcome. The primary approach utilized was inverse variance weighted. To correct for multiple testing, the false discovery rate (FDR) was employed. For sensitivity analysis, an array of robust MR methods was utilized. We found genetically predicted significant association between reduced RNFL thickness and a reduced risk of constipation in PD (odds ratio [OR] = 0.854, 95% confidence interval [CI] (0.782, 0.933), P < 0.001, FDR-corrected P = 0.018). Genetically predicted reduced RNFL thickness was associated with a reduced Unified Parkinson's Disease Rating Scale total score (β = -0.042, 95% CI (-0.079, 0.005), P = 0.025), and reduced GCIPL thickness was associated with a lower risk of constipation (OR = 0.901, 95% CI (0.821, 0.988), P = 0.027) but a higher risk of depression (OR = 1.103, 95% CI (1.016, 1.198), P = 0.020), insomnia (OR = 1.090, 95% CI (1.013, 1.172), P = 0.021), and rapid eye movement sleep behaviour disorder (RBD) (OR = 1.198, 95% CI (1.061, 1.352), P = 0.003). In conclusion, we identify an association between retinal thickness and non-motor symptoms (constipation, depression, insomnia and RBD) in PD, highlighting the potential of retinal thickness as a biomarker for PD nonmotor symptoms. 10.1038/s41531-023-00611-z
Physical activity and Parkinson's disease: a two-sample Mendelian randomisation study. Baumeister Sebastian,Meisinger Christa,Leitzmann Michael,Teumer Alexander,Bahls Martin,Karch André,Baurecht Hansjörg Journal of neurology, neurosurgery, and psychiatry 10.1136/jnnp-2020-324515
Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nature neuroscience Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer's disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases. 10.1038/s41593-021-00886-6
Bidirectional Mendelian randomization to explore the causal relationships between Sleep traits, Parkinson's disease and Amyotrophic lateral sclerosis. Sleep medicine OBJECTIVE:Sleep disturbances have been linked with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) in observational studies, and the comorbidity of PD and ALS has been reported in clinical case reports, but the causalities remain unclear. This study aims to examine bidirectional causal relationships between sleep traits, PD and ALS. METHODS:Bidirectional two sample Mendelian randomisation (MR) analyses were conducted, with data from individuals of mainly European ancestry. Genetic instruments were obtained from the largest published genome-wide association studies (GWAS) concerning various sleep traits, PD and ALS. MR estimates from each genetic instrument were combined by inverse variance weighted method, with alternate methods (eg, weighted median, MR Egger, MR-PRESSO) and statistical graphs to assess horizontal pleiotropy and remove outliers. RESULTS:MR analysis failed to observe any causal association between sleep disorders and PD, but found a possible causal effect of PD risk on ALS risk (odds ratio [OR] = 1.07; 95% CI: 1.01-1.14, P < 0.01), albeit with a horizontal pleiotropy. Furthermore, MR analyses indicated that excessive daytime sleepiness (EDS) (OR = 2.29; 95% CI: 1.04-5.03, P = 0.04) contributed to a modest increase in risk of ALS, but the reverse causalities were not significant. Higher risk of ALS may be associated with being a "morning person" (OR = 1.03, P = 0.02), a longer sleep duration (OR = 1.01, P < 0.01), and a mean of 9 h or more total sleep duration (β = 0.02, P = 0.04). CONCLUSIONS:Aided by large-scale GWAS, a shortage of evidence supporting causal relationships of sleep traits and PD risk, while significant evidence supports that EDS, higher PD risk may causally influence ALS risk. Future researches are required to explore the underlying pathological mechanism as well as the clinically significance, and replicate our findings using independent samples when data become available. 10.1016/j.sleep.2022.03.024
Rheumatoid arthritis decreases risk for Parkinson's disease: a Mendelian randomization study. Li ChunYu,Ou RuWei,Shang HuiFang NPJ Parkinson's disease Epidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson's disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: -0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866-0.943, P: 2.95E-06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD. 10.1038/s41531-021-00166-x
Intelligence, education level, and risk of Parkinson's disease in European populations: A Mendelian randomization study. Frontiers in genetics A high level of education or intelligence (IQ) is reported to be a risk factor for Parkinson's disease (PD). The purpose of this study was to systematically examine the causal relationships between IQ, educational attainment (EA), cognitive performance, and PD. We used summary statistics from genome-wide association studies on IQ, EA, cognitive performance, and PD. Four genome-wide association study (GWAS) data for PD were used to comprehensively explore the causal relationship, including PD GWAS (regardless of sex), age at onset of PD GWAS, male with PD GWAS, and female with PD GWAS data. We conducted a two sample Mendelian randomization (MR) study using the inverse-variance weighted (IVW), weighted median, simple mode, and weighted mode methods to evaluate the causal association between these factors. MR-Egger and MR-PRESSO were used for sensitivity analysis to test and correct horizontal pleiotropy. Multivariate MR (MVMR) was also used to account for the covariation between IQ, EA, and cognition, as well as to explore potential mediating factors. Genetically predicted higher IQ was associated with an increased risk of PD in the entire population, regardless of gender. In the analyses using the IVW method, the odds ratio was 1.37 ( = 0.0064). Men with a higher IQ, more years of education, or stronger cognitive ability are more likely to develop PD compared to women. MVMR showed that adjusting for education and cognition largely attenuated the association between IQ and PD, suggesting that education and cognition may mediate the effect of IQ on PD. This study provides genetic support for the causal link between higher IQ and an increased risk of PD. 10.3389/fgene.2022.963163
Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study. Frontiers in immunology Background:C-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions. Methods:We used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks. Results:We found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population ( < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson's disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders). Conclusions:Genetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions. 10.3389/fimmu.2021.720876
Association between telomere length and Parkinson's disease: a Mendelian randomization study. Chen Ruoqing,Zhan Yiqiang Neurobiology of aging In this study, we examined the potential association of telomere length with Parkinson's disease (PD) using the publicly available genome-wide association study summary statistics from the International Parkinson's Disease Genomics Consortium involving up to 37,688 patients with PD and 449,056 controls in Mendelian randomization framework. The Mendelian randomization approach has the potential to investigate a causal relationship between a risk factor and a disease, avoiding confounding and reverse causation that often present in conventional epidemiological studies. We did not find that longer telomeres were associated with higher risks of PD (odds ratio: 1.18, 95% confidence interval: 0.94, 1.48, p = 0.15). Our study, therefore, did not provide evidence to support a potential causal relationship between telomere length and PD. 10.1016/j.neurobiolaging.2020.07.019
Risky behaviors and Parkinson disease: A mendelian randomization study. Grover Sandeep,Lill Christina M,Kasten Meike,Klein Christine,Del Greco M Fabiola,König Inke R Neurology OBJECTIVE:To examine causal associations between risky behavior phenotypes and Parkinson disease using a mendelian randomization approach. METHODS:We used 2-sample mendelian randomization to generate unconfounded estimates using summary statistics from 2 independent, large meta-analyses of genome-wide association studies on risk-taking behaviors (n = 370,771-939,908) and Parkinson disease (cases n = 9,581, controls n = 33,245). We used the inverse variance weighted method as the main method for judging causality. RESULTS:Our results support a strong protective association between the tendency to smoke and Parkinson disease (odds ratio [OR] 0.714 per log odds of ever smoking, 95% confidence interval [CI] 0.568-0.897, = 0.0041, Cochran Q test = 0.238; index 6.3%). Furthermore, we observed risk association trends between automobile speed propensity and the number of sexual partners and Parkinson disease after removal of overlapping loci with other risky traits (OR 1.986 for each 1-SD increase in normalized automobile speed propensity, 95% CI 1.215-3.243, = 0.0066; OR 1.635 for each 1-SD increase in number of sexual partners, 95% CI 1.165-2.293, = 0.0049). CONCLUSION:These findings provide support for a causal relationship between general risk tolerance and Parkinson disease and may provide new insights into the pathogenic mechanisms leading to the development of Parkinson disease. 10.1212/WNL.0000000000008245
Association between 23 drugs and Parkinson's disease: A two-sample Mendelian randomization study. Brain and behavior BACKGROUND:Parkinson's disease (PD) is a common degenerative nervous system disease. At present, there are certain limitations in various treatment options aimed at preventing or delaying the progression of PD. Therefore, the exploration of new drugs for PD is beneficial. Mendelian randomization (MR) analysis can be used to explore the association between drugs and diseases. In this study, MR analysis was adopted to investigate the causal relationship between 23 drugs and PD. These drugs have been approved for the treatment of different diseases, such as salicylic acid and derivatives (collectively called salicylates, e.g., aspirin, used for fever and pain relief), antithrombotic agents (e.g., warfarin, aspirin, used for preventing thrombotic events). METHODS:The GWAS data for the 23 drugs were obtained from the UK Biobank (UKB) project, while the GWAS data for PD were sourced from FinnGen. Single-Nucleotide Polymorphisms (SNPs) were selected as instrumental variables (IVs). We first performed a series of quality control steps (including MR-PRESSO) to select the appropriate SNPs. Two-sample MR analysis was performed using five different methods, including inverse variance weighting (IVW) with random-effects model, weighted median, MR-Egger, simple model, and weighted model. At the same time, sensitivity analysis was carried out using the MR-Egger and Cochran's Q test to ensure the authenticity and reliability of the results. RESULTS:In MR-PRESSO, salicylates and antithrombotic agents showed statistically significant associations with PD, respectively. In the main MR analysis (IVW), there was a negative causal relationship between salicylates and PD (OR = 0.73, 95% CI = 0.54-0.98, p = .039). Similarly, there was a negative causal relationship between antithrombotic agents and PD (OR = 0.70, 95%CI = 0.52-0.96, p = .027). No statistically significant association was found between the remaining 21 drugs and PD. CONCLUSION:This MR study demonstrated that salicylates and antithrombotic agents can reduce the risk of PD, thus providing a novel avenue for future drug exploration in PD. 10.1002/brb3.3225
Are neurodegenerative diseases associated with an increased risk of inflammatory bowel disease? A two-sample Mendelian randomization study. Frontiers in immunology Background:Several studies have shown that neurodegenerative diseases (e.g., Parkinson's disease [PD] and Alzheimer's disease [AD]) are associated with inflammatory bowel disease (IBD), but the causality and direction of their associations remain unclear. Mendelian randomization (MR) studies have explored the causal effects of IBD on PD and AD. However, only a few studies examined this reverse association. Thus, this study aimed to explore whether there are causal associations of genetically predicted PD and AD with IBD, using a two-sample MR study. Methods:Summary statistics for IBD, ulcerative colitis (UC), and Crohn's disease (CD) were derived from a genome-wide association study (GWAS) meta-analysis, which included the International IBD Genetics Consortium and the UK IBD Genetics Consortium (n=59,957). Genetic variants associated with the largest meta-analysis of GWAS of PD (n=1,474,097) and AD (n=455,258) were used as instrumental variables. We used multiple methods, including inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, weighted mode, and Robust Adjusted Profile Score (RAPS) methods, to estimate the effects of genetically predicted PD and AD on IBD. To confirm the validity of the analysis, we also evaluated the pleiotropic effects, heterogeneity, and leave-one-out sensitivity analysis that drive causal associations. Results:The results of the IVW method, WM, and RAPS showed that genetically predicted PD was significantly associated with an increased risk of UC (odds ratio []=1.068, =1.107, =1.069, all <0.05). Additionally, we found that there were significant associations of genetically predicted PD with CD ( =1.064, =1.065, all <0.05) and IBD ( =1.062, =1.063, all <0.05) using the IVW method and RAPS. However, there was no significant causal evidence of genetically predicted AD in IBD, UC, or CD among all MR methods. In all MR analyses, there were no horizontal pleiotropy (all >0.05), or statistical heterogeneity. The sensitivity analysis results of the leave-one-out sensitivity analysis showed that the causal effect estimations of genetically predicted PD and AD on IBD were robust. Conclusions:Our MR study corroborated a causal association between genetically predicted PD and IBD but did not support a causal effect of genetically predicted AD on IBD. More animal experiments or population-based observational studies are required to clarify the underlying mechanisms of PD and IBD. 10.3389/fimmu.2022.956005
Unhealthy Behaviours and Risk of Parkinson's Disease: A Mendelian Randomisation Study. Journal of Parkinson's disease BACKGROUND:Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson's disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. OBJECTIVE:Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. METHODS:19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. RESULTS:Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921-0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025-1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979-0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. CONCLUSION:Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small. 10.3233/JPD-202487
Serum Calcium Levels and Parkinson's Disease: A Mendelian Randomization Study. Frontiers in genetics BACKGROUND:Though increasing epidemiological studies have evaluated the correlation between serum calcium contents and Parkinson's disease (PD), the results are inconsistent. At present, whether there is a causal association between serum calcium content and PD remains undetermined. OBJECTIVE AND METHODS:This study was designed to explore the relationship between increased serum calcium contents and PD risk. In this present study, a Mendelian randomization trial was carried out using a large-scale serum calcium genome-wide association study (GWAS) dataset ( = 61,079, Europeans) and a large-scale PD GWAS dataset ( = 8,477, Europeans including 4,238 PD patients and 4,239 controls). Here, a total of four Mendelian randomization methods comprising weighted median, inverse-variance weighted meta-analysis (IVW), MR-Egger, and MR-PRESSO were used. RESULTS:Our data concluded that genetically higher serum calcium contents were not significantly related to PD. CONCLUSION:In conclusion, we provided genetic evidence that there was no direct causal relationship between serum calcium contents and PD. Hence, calcium supplementation may not result in reduced PD risk. 10.3389/fgene.2020.00824
Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies. BMC medicine BACKGROUND:Obesity is a worldwide epidemic that has been associated with a plurality of diseases in observational studies. The aim of this study was to summarize the evidence from Mendelian randomization (MR) studies of the association between body mass index (BMI) and chronic diseases. METHODS:PubMed and Embase were searched for MR studies on adult BMI in relation to major chronic diseases, including diabetes mellitus; diseases of the circulatory, respiratory, digestive, musculoskeletal, and nervous systems; and neoplasms. A meta-analysis was performed for each disease by using results from published MR studies and corresponding de novo analyses based on summary-level genetic data from the FinnGen consortium (n = 218,792 individuals). RESULTS:In a meta-analysis of results from published MR studies and de novo analyses of the FinnGen consortium, genetically predicted higher BMI was associated with increased risk of type 2 diabetes mellitus, 14 circulatory disease outcomes, asthma, chronic obstructive pulmonary disease, five digestive system diseases, three musculoskeletal system diseases, and multiple sclerosis as well as cancers of the digestive system (six cancer sites), uterus, kidney, and bladder. In contrast, genetically predicted higher adult BMI was associated with a decreased risk of Dupuytren's disease, osteoporosis, and breast, prostate, and non-melanoma cancer, and not associated with Alzheimer's disease, amyotrophic lateral sclerosis, or Parkinson's disease. CONCLUSIONS:The totality of the evidence from MR studies supports a causal role of excess adiposity in a plurality of chronic diseases. Hence, continued efforts to reduce the prevalence of overweight and obesity are a major public health goal. 10.1186/s12916-021-02188-x
Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets. JAMA neurology Importance:Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective:To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting:This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures:It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results:Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance:Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies. 10.1001/jamaneurol.2020.5257
Health effects of milk consumption: phenome-wide Mendelian randomization study. BMC medicine BACKGROUND:We performed phenome-wide Mendelian randomization analysis (MR-PheWAS), two-sample MR analysis, and systemic review to comprehensively explore the health effects of milk consumption in the European population. METHODS:Rs4988235 located upstream of the LCT gene was used as the instrumental variable for milk consumption. MR-PheWAS analysis was conducted to map the association of genetically predicted milk consumption with 1081 phenotypes in the UK Biobank study (n=339,197). The associations identified in MR-PheWAS were examined by two-sample MR analysis using data from the FinnGen study (n=260,405) and international consortia. A systematic review of MR studies on milk consumption was further performed. RESULTS:PheWAS and two-sample MR analyses found robust evidence in support of inverse associations of genetically predicted milk consumption with risk of cataract (odds ratio (OR) per 50 g/day increase in milk consumption, 0.89, 95% confidence interval (CI), 0.84-0.94; p=3.81×10), hypercholesterolemia (OR, 0.91, 95% CI 0.86-0.96; p=2.97×10), and anal and rectal polyps (OR, 0.85, 95% CI, 0.77-0.94; p=0.001). An inverse association for type 2 diabetes risk (OR, 0.92, 95% CI, 0.86-0.97; p=0.003) was observed in MR analysis based on genetic data with body mass index adjustment but not in the corresponding data without body mass index adjustment. The systematic review additionally found evidence that genetically predicted milk consumption was inversely associated with asthma, hay fever, multiple sclerosis, colorectal cancer, and Alzheimer's disease, and positively associated with Parkinson's disease, renal cell carcinoma, metabolic syndrome, overweight, and obesity. CONCLUSIONS:This study suggests several health effects of milk consumption in the European population. 10.1186/s12916-022-02658-w
Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Large-scale genome-wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported risk variants confer risk of PD. OBJECTIVE:To nominate genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. METHODS:We conducted a two-sample Mendelian randomization (MR) study by integrating large-scale genome-wide associations and expression quantitative trait loci (eQTL) data from dopaminergic neurons. RESULTS:MR analysis nominated 10 risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. These MR significant genes include FAM200B, NDUFAF2, NUP42, SH3GL2, STX1B, CCDC189, KAT8, PRSS36, VAMP4, and ZSWIM7. CONCLUSIONS:We report the first MR study of PD by using dopaminergic neuron-specific eQTL and nominate novel risk genes for PD. Further functional characterization of the nominated risk genes will provide mechanistic insights into PD pathogenesis and potential therapeutic targets. © 2022 International Parkinson and Movement Disorder Society. 10.1002/mds.29239
mTORC1-Dependent Protein and Parkinson's Disease: A Mendelian Randomization Study. Brain sciences BACKGROUND:The mTOR pathway is crucial in controlling the growth, differentiation, and survival of neurons, and its pharmacological targeting has promising potential as a treatment for Parkinson's disease. However, the function of mTORC1 downstream proteins, such as RPS6K, EIF4EBP, EIF-4E, EIF-4G, and EIF4A, in PD development remains unclear. METHODS:We performed a Mendelian randomization study to evaluate the causal relationship between mTORC1 downstream proteins and Parkinson's disease. We utilized various MR methods, including inverse-variance-weighted, weighted median, MR-Egger, MR-PRESSO, and MR-RAPS, and conducted sensitivity analyses to identify potential pleiotropy and heterogeneity. RESULTS:The genetic proxy EIF4EBP was found to be inversely related to PD risk (OR = 0.79, 95% CI = 0.67-0.92, = 0.003), with the results from WM, MR-PRESSO, and MR-RAPS being consistent. The plasma protein levels of EIF4G were also observed to show a suggestive protective effect on PD (OR = 0.85, 95% CI = 0.75-0.97, = 0.014). No clear causal effect was found for the genetically predicted RP-S6K, EIF-4E, and EIF-4A on PD risk. Sensitivity analyses showed no significant imbalanced pleiotropy or heterogeneity, indicating that the MR estimates were robust and independent. CONCLUSION:Our unbiased MR study highlights the protective role of serum EIF4EBP levels in PD, suggesting that the pharmacological activation of EIF4EBP activity could be a promising treatment option for PD. 10.3390/brainsci13040536
The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study. Journal of neuroinflammation BACKGROUND:Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. METHOD:Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. RESULTS:We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012-1.119, P = 0.014, P = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016-1.072, P = 0.002, P = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. CONCLUSIONS:Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy. 10.1186/s12974-022-02582-z
Relationship between Parkinson's disease and cardio-cerebrovascular diseases: a Mendelian randomized study. Scientific reports Parkinson's disease (PD) and cardio-cerebrovascular diseases are related, according to earlier studies, but these studies have some controversy. Our aim was to assess the impact of PD on cardiocerebrovascular diseases using a Mendelian randomization (MR) method. The data for PD were single nucleotide polymorphisms (SNPs) from a publicly available genome-wide association study (GWAS) dataset containing data on 482,730 individuals. And the outcome SNPs data is were derived from five different GWAS datasets. The basic method for MR analysis was the inverse variance weighted (IVW) approach. We use the weighted median method and the MR-Egger method to supplement the MR analysis conclusion. Finally, We used Cochran's Q test to test heterogeneity, MR-PRESSO method and leave-one-out analysis method to perform sensitivity analysis. We used ratio ratios (OR) to assess the strength of the association between exposure and outcome, and 95% confidence intervals (CI) to show the reliability of the results. Our findings imply that PD is linked to a higher occurrence of coronary artery disease (CAD) (OR = 1.055, 95% CI 1.020-1.091, P = 0.001), stroke (OR = 1.039, 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and cardioembolic stroke (CES) also yielded positive results, respectively (OR = 1.043, 95% CI 1.008-1.079, P = 0.013), (OR = 1.076, 95% CI 1.008-1.149, P = 0.026). There is no evidence of a relationship between PD and other cardio-cerebrovascular diseases. Additionally, sensitivity analysis revealed reliable outcomes. Our MR study analysis that PD is related with an elevated risk of CAD, stroke, IS, and CES. 10.1038/s41598-023-47708-2
A proteogenomic view of Parkinson's disease causality and heterogeneity. NPJ Parkinson's disease The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration. 10.1038/s41531-023-00461-9
Lipid-lowering drug targets and Parkinson's disease: A sex-specific Mendelian randomization study. Frontiers in neurology Parkinson's disease (PD) affects millions of individuals worldwide, and it is the second most common late-onset neurodegenerative disorder. There is no cure and current treatments only alleviate symptoms. Modifiable risk factors have been explored as possible options for decreasing risk or developing drug targets to treat PD, including low-density lipoprotein cholesterol (LDL-C). There is evidence of sex differences for cholesterol levels as well as for PD risk. Genetic datasets of increasing size are permitting association analyses with increased power, including sex-stratified analyses. These association results empower Mendelian randomization (MR) studies, which, given certain assumptions, test whether there is a causal relationship between the risk factor and the outcome using genetic instruments. Sex-specific causal inference approaches could highlight sex-specific effects that may otherwise be masked by sex-agnostic approaches. We conducted a sex-specific two-sample cis-MR analysis based on genetic variants in LDL-C target encoding genes to assess the impact of lipid-lowering drug targets on PD risk. To complement the cis-MR analysis, we also conducted a sex-specific standard MR analysis (using genome-wide independent variants). We did not find evidence of a causal relationship between LDL-C levels and PD risk in females [OR (95% CI) = 1.01 (0.60, 1.69), IVW random-effects] or males [OR (95% CI) = 0.93 (0.55, 1.56)]. The sex-specific standard MR analysis also supported this conclusion. We encourage future work assessing sex-specific effects using causal inference techniques to better understand factors that may contribute to complex disease risk differently between the sexes. 10.3389/fneur.2022.940118
Bidirectional Mendelian randomization study of psychiatric disorders and Parkinson's disease. Frontiers in aging neuroscience Introduction:Although the relationship between psychiatric disorders and Parkinson's disease (PD) has attracted continuous research attention, the causal linkage between them has not reached a definite conclusion. Methods:To identify the causal relationship between psychiatric disorders and PD, we used public summary-level data from the most recent and largest genome-wide association studies (GWASs) on psychiatric disorders and PD to conduct a bidirectional two-sample Mendelian randomization (MR). We applied stringent control steps in instrumental variable selection using the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) method to rule out pleiotropy. The inverse-variance weighted (IVW) method was used to identify the causal relationship between psychiatric disorders and PD. Multiple MR analysis methods, including MR-Egger, weighted-median, and leave-one-out analyses, were used for sensitivity analysis, followed by heterogeneity tests. Further validation and reverse MR analyses were conducted to strengthen the results of the forward MR analysis. Results:The lack of sufficient estimation results could suggest a causal relationship between psychiatric disorders and PD in the forward MR analysis. However, the subsequent reverse MR analysis detected a causal relationship between PD and bipolar disorder (IVW: odds ratios [OR] =1.053, 95% confidence interval [CI] =1.02-1.09,  = 0.001). Further analysis demonstrated a causal relationship between genetically predicted PD and the risk of bipolar disorder subtype. No pleiotropy or heterogeneity was detected in the analyses. Discussion:Our study suggested that while psychiatric disorders and traits might play various roles in the risk of developing PD, PD might also be involved in the risk of developing psychiatric disorders. 10.3389/fnagi.2023.1120615
Mineral Nutrition and the Risk of Chronic Diseases: A Mendelian Randomization Study. Cheng Wen-Wen,Zhu Qiang,Zhang Hong-Yu Nutrients We applied Mendelian randomization analyses to investigate the potential causality between blood minerals (calcium, magnesium, iron, copper, and zinc) and osteoporosis (OP), gout, rheumatoid arthritis (RA), type 2 diabetes (T2D), Alzheimer's disease (AD), bipolar disorder (BD), schizophrenia , Parkinson's disease and major depressive disorder. Single nucleotide polymorphisms (SNPs) that are independent (² < 0.01) and are strongly related to minerals ( < 5 × 10) are selected as instrumental variables. Each standard deviation increase in magnesium (0.16 mmol/L) is associated with an 8.94-fold increase in the risk of RA ( = 0.044) and an 8.78-fold increase in BD ( = 0.040) but a 0.10 g/cm² increase in bone density related to OP ( = 0.014). Each per-unit increase in copper is associated with a 0.87-fold increase in the risk of AD ( = 0.050) and BD ( = 0.010). In addition, there is suggestive evidence that calcium is positively correlated (OR = 1.36, = 0.030) and iron is negatively correlated with T2D risk (OR = 0.89, = 0.010); both magnesium (OR = 0.26, = 0.013) and iron (OR = 0.71, = 0.047) are negatively correlated with gout risk. In the sensitivity analysis, causal estimation is not affected by pleiotropy. This study supports the long-standing hypothesis that magnesium supplementation can increase RA and BD risks and decrease OP risk and that copper intake can reduce AD and BD risks. This study will be helpful to address some controversial debates on the relationships between minerals and chronic diseases. 10.3390/nu11020378
Ovarian Cancer and Parkinson's Disease: A Bidirectional Mendelian Randomization Study. Journal of clinical medicine (1) Background: Ovarian cancer (OC) and Parkinson's disease (PD) represent a huge public health burden. The relationship of these two diseases is suggested in the literature while not fully understood. To better understand this relationship, we conducted a bidirectional Mendelian ran-domization analysis using genetic markers as a proxy. (2) Methods: Utilizing single nucleotide polymorphisms associated with PD risk, we assessed the association between genetically predicted PD and OC risk, overall and by histotypes, using summary statistics from previously conducted genome-wide association studies of OC within the Ovarian Cancer Association Consortium. Similarly, we assessed the association between genetically predicted OC and PD risk. The inverse variance weighted method was used as the main method to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations of interest. (3) Results: There was no significant association between genetically predicted PD and OC risk: OR = 0.95 (95% CI: 0.88-1.03), or between genetically predicted OC and PD risk: OR = 0.80 (95% CI: 0.61-1.06). On the other hand, when examined by histotypes, a suggestive inverse association was observed between genetically predicted high grade serous OC and PD risk: OR = 0.91 (95% CI: 0.84-0.99). (4) Conclusions: Overall, our study did not observe a strong genetic association between PD and OC, but the observed potential association between high grade serous OC and reduced PD risk warrants further investigation. 10.3390/jcm12082961
Associations between gut microbiota and Parkinson disease: A bidirectional Mendelian randomization analysis. European journal of neurology BACKGROUND AND PURPOSE:Parkinson disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans. METHODS:We performed two-sample bidirectional Mendelian randomization using summary statistics from the international consortium MiBioGen (N = 18,340), the Framingham Heart Study (N = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD age at onset (17,996 cases). RESULTS:Twelve microbiota features presented suggestive associations with PD risk or age at onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio = 0.77, 95% confidence interval [CI] = 0.60-0.99, p = 0.040). Conversely, high levels of five short-chain fatty acid (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age at PD onset. Gut production of serotonin was associated with an earlier age at PD onset (beta = -0.64, 95% CI = -1.15 to -0.13, p = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition. CONCLUSIONS:These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation. 10.1111/ene.15848
Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study. Kang Xiaoying,Ploner Alexander,Pedersen Nancy L,Bandres-Ciga Sara,Noyce Alastair J,Wirdefeldt Karin,Williams Dylan M Neurology OBJECTIVE:To evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics. METHODS:Genetic variants in the vicinity of , the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (n/ = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975). RESULTS:TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91-1.08) or age at onset (0.13 years later onset; 95% CI -0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65-0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74-0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36-1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators. CONCLUSIONS:Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD. 10.1212/WNL.0000000000011630
Brain Proteome-Wide and Transcriptome-Wide Asso-ciation Studies, Bayesian Colocalization, and Mendelian Randomization Analyses Reveal Causal Genes of Parkinson's Disease. The journals of gerontology. Series A, Biological sciences and medical sciences How genome-wide associated loci confer risk for Parkinson's disease is unclear. We aim to reveal causal genes through effects on brain proteins to provide new pathogenesis insights for Parkinson's disease. Proteome-wide and transcriptome-wide associations were determined by functional summary-based imputation leveraging data from genome-wide association summary (56 306 Europeans, 1.4 million controls), brain proteomes (528 cases from 2 separate data sets), and transcriptome (452 cases), followed by Mendelian randomization, Bayesian colocalization, cell-type-specific and brain regional expression, and drug-gene interaction analyses. As a result, genetically regulated protein abundances of 11 genes were associated with Parkinson's disease. Five genes (CD38, GPNMB, TMEM175, RAB7L1, and HIP1R) were colocalized. Four genes (GPNMB, SEC23IP, CD38, and DGKQ) demonstrated Mendelian randomized correlations (p < 8.10 × 10-5). Higher GPNMB level (1.47, 1.28-1.68) and lower CD38 level (0.319, 0.24-0.43) were causally associated with higher risk of Parkinson's disease, consistent with transcriptomic evaluations. CD38 and GPNMB were preferentially enriched in astrocytes and oligodendrocyte precursor cells, respectively. And CD38 and GPNMB were suggested to be the targets of many oncological drugs from Drug-Gene Interaction database. In conclusion, utilizing multidimensional data, GPNMB and CD38 were prioritized as the causal genes of Parkinson's disease, crucial for mechanistic and therapeutic investigations. 10.1093/gerona/glac245
Mendelian Randomization Studies of Coffee and Caffeine Consumption. Nutrients Habitual coffee and caffeine consumption has been reported to be associated with numerous health outcomes. This perspective focuses on Mendelian Randomization (MR) approaches for determining whether such associations are causal. Genetic instruments for coffee and caffeine consumption are described, along with key concepts of MR and particular challenges when applying this approach to studies of coffee and caffeine. To date, at least fifteen MR studies have investigated the causal role of coffee or caffeine use on risk of type 2 diabetes, cardiovascular disease, Alzheimer's disease, Parkinson's disease, gout, osteoarthritis, cancers, sleep disturbances and other substance use. Most studies provide no consistent support for a causal role of coffee or caffeine on these health outcomes. Common study limitations include low statistical power, potential pleiotropy, and risk of collider bias. As a result, in many cases a causal role cannot confidently be ruled out. Conceptual challenges also arise from the different aspects of coffee and caffeine use captured by current genetic instruments. Nevertheless, with continued genome-wide searches for coffee and caffeine related loci along with advanced statistical methods and MR designs, MR promises to be a valuable approach to understanding the causal impact that coffee and caffeine have in human health. 10.3390/nu10101343
Sleep behaviors and Parkinson's disease: A bidirectional Mendelian randomization analysis. Behavioural brain research OBJECTIVE:Whether the quantity and quality of sleep are the risk factors for the development of Parkinson's disease remains unclear though it has now been confirmed that the quality of sleep among patients with Parkinson's disease is affected at the prodromal and clinical stages. Accordingly, this study aimed to examine the bidirectional causal relationships of multiple sleep-related phenotypes with Parkinson's disease using a two-sample Mendelian randomization (MR) method. METHODS:The summary-level data collected from the published genome-wide association studies was used for analysis. Besides, the genetic relationships between different sleep-related phenotypes, including self-reported and accelerometer measured traits, were estimated for the risk and age at the onset of Parkinson's disease. To conduct MR analysis, inverse variance weighted, weight median, MR-Egger, and MR-PRESSO method were mainly used. Moreover, sensitivity analyses were carried out to examine the pleiotropic effect. RESULTS:In general, there was insufficient evidence to support the causal effect of sleep-related phenotypes on risk (N cases/controls = 33,674/449,056) and age at the onset (N cases = 28,568) of Parkinson's disease. However, the results of this study indicated that the later onset age of Parkinson's disease was related to the frequent occurrence of insomnia (OR [95% CI] 1.007 [1.003, 1.011], P < 0.001) after the adjustment for multiple testing. CONCLUSIONS:The results of this study suggest that insomnia-associated single nucleotide polymorphisms are more frequent in later onset Parkinson's disease patients compared to earlier onset patients. However, given the limitations of statistical power and potential bias, further validation should be still conducted through larger population research. 10.1016/j.bbr.2022.114281
COVID-19 and risk of neurodegenerative disorders: A Mendelian randomization study. Translational psychiatry Emerging evidence has suggested a close correlation between COVID-19 and neurodegenerative disorders. However, whether there exists a causal association and the effect direction remains unknown. To examine the causative role of COVID-19 in the risk of neurodegenerative disorders, we estimated their genetic correlation, and then conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of susceptibility, hospitalization, and severity of COVID-19, as well as six major neurodegenerative disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, multiple sclerosis, and Parkinson's disease. We identified a significant and positive genetic correlation between hospitalization of COVID-19 and AD (genetic correlation: 0.23, P = 8.36E-07). Meanwhile, hospitalization of COVID-19 was significantly associated with a higher risk of AD (OR: 1.02, 95% CI: 1.01-1.03, P: 1.19E-03). Consistently, susceptibility (OR: 1.05, 95% CI: 1.01-1.09, P: 9.30E-03) and severity (OR: 1.01, 95% CI: 1.00-1.02, P: 0.012) of COVID-19 were nominally associated with higher risk of AD. The results were robust under all sensitivity analyses. These results demonstrated that COVID-19 could increase the risk of AD. Future development of preventive or therapeutic interventions could attach importance to this to alleviate the complications of COVID-19. 10.1038/s41398-022-02052-3
Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study. Journal of Alzheimer's disease : JAD BACKGROUND:Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. OBJECTIVE:Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. METHODS:We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. RESULTS:Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. CONCLUSION:Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms. 10.3233/JAD-215411
Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies. EBioMedicine BACKGROUND:The causal association between cigarette smoking and several diseases remains equivocal. The purpose of this study was to appraise the causal role of smoking in a wide range of diseases by summarizing the evidence from Mendelian randomization (MR) studies. METHODS:MR studies on genetic liability to smoking initiation or lifetime smoking (composite of smoking initiation, heaviness, duration, and cessation) in relation to circulatory system, digestive system, nervous system, musculoskeletal system, endocrine, metabolic, and eye diseases, and neoplasms published until February 15, 2022, were identified in PubMed. De novo MR analyses were performed using summary statistics data from genome-wide association studies. Meta-analysis was applied to combine study-specific estimates. FINDINGS:Meta-analyses of findings of 29 published MR studies and 123 de novo MR analyses of 57 distinct primary outcomes showed that genetic liability to smoking (smoking initiation or lifetime smoking) was associated with increased risk of 13 circulatory system diseases, several digestive system diseases (including diverticular, gallstone, gastroesophageal reflux, and Crohn's disease, acute pancreatitis, and periodontitis), epilepsy, certain musculoskeletal system diseases (including fracture, osteoarthritis, and rheumatoid arthritis), endocrine (polycystic ovary syndrome), metabolic (type 2 diabetes) and eye diseases (including age-related macular degeneration and senile cataract) as well as cancers of the lung, head and neck, esophagus, pancreas, bladder, kidney, cervix, and ovaries, and myeloid leukemia. Smoking liability was associated with decreased risk of Parkinson's disease and prostate cancer. INTERPRETATION:This study found robust evidence that cigarette smoking causes a wide range of diseases. FUNDING:This work was supported by research grants from the Swedish Cancer Society (Cancerfonden), the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Research Council (Vetenskapsrådet, 2019-00977). Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. 10.1016/j.ebiom.2022.104154
Parkinson's Disease and Ischemic Stroke: a Bidirectional Mendelian Randomization Study. Translational stroke research We aimed to assess the potential causal association between Parkinson's disease (PD) and ischemic stroke (IS) with Mendelian randomization methods. Summary statistics data from two large-scale genome-wide association studies (GWAS) for 33,674 PD cases and 40,585 IS cases were used in this study. We used inverse variance-weighted method for primary analysis, and four other Mendelian randomization methods (weighted median, MR-Egger regression methods, robust adjusted profile score, radial regression) to test whether PD was causal for IS and its subtypes. Analyses were bidirectional to assess reverse causality. Primary analysis showed PD had a significantly causal association with IS (OR 1.04; 95% CI, 1.02-1.07; p = 0.0019), and two subtypes of IS, cardioembolic stroke (OR 1.11; 95% CI, 1.06-1.18; p = 0.0001) and large artery stroke (OR 1.08; 95% CI, 1.01-1.15; p = 0.034), but not with small-vessel stroke (p = 0.180). The point estimates from sensitivity analyses were in the same direction. There was no strong evidence for a reverse causal association between PD and IS. Using multiple Mendelian randomization methods based on large-scale GWAS, PD is a potential cause of cardioembolic stroke and large artery stroke, but not small-vessel stroke. Ischemic stroke does not cause PD. 10.1007/s12975-021-00974-6
Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease. Journal of Parkinson's disease BACKGROUND:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. 10.3233/JPD-212851
Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study. Nutrients We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer's disease and Parkinson's disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer's Project, the International Parkinson's Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson's disease in the FinnGen consortium. but not in the International Parkinson's Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer's disease. The association between caffeine and Parkinson's disease requires further study. 10.3390/nu14091697
Association between inflammatory bowel disease and Parkinson's disease: A Mendelian randomization study. NPJ Parkinson's disease Emerging evidence from observational studies suggests an increased risk of Parkinson's disease (PD) in patients with inflammatory bowel disease (IBD). However, to date it is not clear whether a causal relationship exists. To investigate whether IBD is causally related to PD, a two-sample Mendelian randomization study was carried out. Independent genetic instruments from the largest available genome-wide association study (GWAS) for IBD (7045 cases, 456,327 controls) including European participants were used to investigate the association with PD (56,306 cases; 1.4 million controls). The results were validated by using a second IBD sample (12,882 cases; 21,770 controls) including the main subtypes ulcerative colitis (UC; 6968 cases; 20,464 controls) and Crohn's disease (CD; 5956 cases; 14,927 controls). The radial inverse-variance weighted (IVW) approach was used in the primary analysis, and the robustness of the findings were confirmed in a number of sensitivity analyses. Finally, the recently proposed CAUSE approach was performed. There was no evidence of an association between IBD and PD (OR = 0.98; 95% CI: [0.93; 1.04]; P = 0.48). This finding could be validated using a second sample of IBD cases (OR = 0.98; 95% CI: [0.95; 1.02]; P = 0.36). Furthermore, MR analyses did not support a causal effect of CD (OR = 1.00; 95% CI: [0.98; 1.03]; P = 0.96) or UC (OR = 1.02; 95% CI: [0.98; 1.06]; P = 0.45) on PD. The present study suggests that neither IBD nor its subtypes CD and UC causally affect Parkinson's disease in the European population. Further research is necessary to investigate whether intestinal inflammation impacts the development of PD. 10.1038/s41531-022-00318-7
Causal Association between Periodontitis and Parkinson's Disease: A Bidirectional Mendelian Randomization Study. Botelho João,Machado Vanessa,Mendes José João,Mascarenhas Paulo Genes The latest evidence revealed a possible association between periodontitis and Parkinson's disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = -0.0003, Standard Error [SE] 0.0003, = 0.26). The eight independent SNPs (B = -0.0000, SE 0.0001, = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = -0.0001, SE 0.0001, = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results. 10.3390/genes12050772
Green Tea Intake and Parkinson's Disease Progression: A Mendelian Randomization Study. Frontiers in nutrition Epidemiological studies have suggested green tea intake was associated with a reduced risk of Parkinson's disease (PD). However, whether green tea intake has an effect on PD progression is unknown. To evaluate the role of green tea intake in PD progression, we conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of green tea intake ( = 64,949), age at onset ( = 28,568) and progression ( = 4,093) of PD. One standard deviation increase in genetically determined green tea intake was significantly associated with slower progression to dementia (OR: 0.87, 95% CI: 0.81-0.94, : 3.48E-04) after the Bonferroni correction. Meanwhile, higher green tea intake was nominally associated with slower progression to depression, and lower risk of dementia, depression, hyposmia and insomnia at baseline. The results were robust under all sensitivity analyses. These results might facilitate novel therapeutic targets to slow down the progression of PD in clinical trials, and have clinical implications for patients with PD. 10.3389/fnut.2022.848223
Psoriasis and progression of Parkinson's disease: a Mendelian randomization study. Journal of the European Academy of Dermatology and Venereology : JEADV BACKGROUND:Epidemiological studies have suggested psoriasis was associated with an increased risk of Parkinson's disease (PD). However, whether psoriasis has an effect on PD progression is not explored yet. OBJECTIVES:To evaluate the causal role of psoriasis in PD progression. METHODS:We conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association study of psoriasis (N = 33 394), age at onset (N = 28 568) and progression (N = 4093) of PD. RESULTS:One standard deviation increase in genetically determined psoriasis risk was significantly associated with faster progression to dementia (OR = 1.07, 95% CI: 0.1.03-1.1, P = 4.71E-04). Meanwhile, higher psoriasis risk was nominally associated with faster progression of PD measured by time to Hoehn and Yahr stage 3 (OR = 1.05, 95% CI: 1.02-1.08, P = 1.53E-03) and depression (OR = 1.06, 95% CI: 1.02-1.11, P = 1.77E-03) of PD. The results were robust under all sensitivity analyses. CONCLUSIONS:These results suggested psoriasis accelerated overall progression of PD, and increased risk of dementia and depression of PD. A deeper understanding of neuroinflammation and immune response is likely to elucidate the potential pathogenesis of PD progression and identify novel therapeutic targets. 10.1111/jdv.18459
Parkinson's disease and Alzheimer's disease: a Mendelian randomization study. BMC medical genetics BACKGROUND:Alzheimer's disease (AD) and Parkinson's disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk. RESULTS:We did not obtain any significant result (OR = 0.918, 95% CI: 0.782-1.076, P = 0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR = 0.638, 95% CI: 0.485-0.838, P = 1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results. CONCLUSION:The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases. 10.1186/s12881-018-0721-7
Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. OBJECTIVE:The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). METHODS:We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). RESULTS:Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029). CONCLUSIONS:Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society. 10.1002/mds.28902
Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome. Nature communications Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development. 10.1038/s41467-021-26280-1
Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. The Lancet. Neurology BACKGROUND:Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. METHODS:We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. FINDINGS:Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10). INTERPRETATION:These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. FUNDING:The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources). 10.1016/S1474-4422(19)30320-5