Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome.
eLife
Background:Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours. Methods:We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343). Results:Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including , , and . The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity. Conclusions:This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas. Funding:Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17-022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).
10.7554/eLife.83118
Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis.
Gastroenterology
BACKGROUND & AIMS:Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD. METHODS:We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization. RESULTS:We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels. CONCLUSIONS:Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.
10.1053/j.gastro.2023.02.023
Investigation of Causal Effects of Protein Biomarkers on Cardiovascular Disease in Persons With HIV.
The Journal of infectious diseases
BACKGROUND:There is an incompletely understood increased risk for cardiovascular disease (CVD) among people with HIV (PWH). We investigated if a collection of biomarkers were associated with CVD among PWH. Mendelian randomization (MR) was used to identify potentially causal associations. METHODS:Data from follow-up in 4 large trials among PWH were used to identify 131 incident CVD cases and they were matched to 259 participants without incident CVD (controls). Tests of associations between 460 baseline protein levels and case status were conducted. RESULTS:Univariate analysis found CLEC6A, HGF, IL-6, IL-10RB, and IGFBP7 as being associated with case status and a multivariate model identified 3 of these: CLEC6A (odds ratio [OR] = 1.48, P = .037), HGF (OR = 1.83, P = .012), and IL-6 (OR = 1.45, P = .016). MR methods identified 5 significantly associated proteins: AXL, CHI3L1, GAS6, IL-6RA, and SCGB3A2. CONCLUSIONS:These results implicate inflammatory and fibrotic processes as contributing to CVD. While some of these biomarkers are well established in the general population and in PWH (IL-6 and its receptor), some are novel to PWH (HGF, AXL, and GAS6) and some are novel overall (CLEC6A). Further investigation into the uniqueness of these biomarkers in PWH and the role of these biomarkers as targets among PWH is warranted.
10.1093/infdis/jiac496
Comparison of intergenerational instrumental variable analyses of body mass index and mortality in UK Biobank.
International journal of epidemiology
BACKGROUND:An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants. METHODS:In Cox regression models, parental BMI was instrumented by offspring BMI using an 'offspring as instrument' (OAI) estimation and by offspring BMI-related genetic variants in a 'proxy-genotype Mendelian randomization' (PGMR) estimation. RESULTS:Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent-offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother-son) and 1.23 (95% CI: 1.16, 1.29; father-daughter). CONCLUSION:Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.
10.1093/ije/dyac159
Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds.
Journal of clinical immunology
PURPOSE:The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD). We aimed to study this Mendelian susceptibility to mycobacterial diseases in Moroccan kindreds through clinical, immunological, and genetic analysis. METHODS:Patients presented with clinical features of MSMD were recruited into this study. We used whole blood samples from patients and age-matched healthy controls. To measure IL-12 and IFN-γ production, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for patients and their relatives. RESULTS:Our study involved 22 cases from 15 unrelated Moroccan kindreds. The average age at diagnosis is 4 years. Fourteen patients (64%) were born to consanguineous parents. All patients were vaccinated with the BCG vaccine, and twelve of them (55%) developed locoregional or disseminated BCG infections. The other symptomatic patients had severe tuberculosis and/or recurrent salmonellosis. Genetic mutations were identified on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in one patient, with different modes of inheritance. All identified mutations/variants altered production or response to IFN-γ or both. CONCLUSION:Severe forms of tuberculosis and complications of BCG vaccination may imply a genetic predisposition present in the Moroccan population. In the presence of these infections, systematic genetic studies became necessary. BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria.
10.1007/s10875-022-01419-x
Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.
EBioMedicine
BACKGROUND:Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. METHODS:We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses. FINDINGS:Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g. , HDL-C: -0.05 SD; 95% CI -0.07 to -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). IVW estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C. In pleiotropy-robust models, T2D liability was still estimated to increase BCAAs, but several estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed substantially by age for non-HDL-C traits, with higher CAD liability lowering LDL-C only at older ages when statin use was common. INTERPRETATION:Overall, our results support largely distinct metabolic features of genetic liability to T2D and CAD, illustrating both challenges and opportunities for preventing these commonly co-occurring diseases. FUNDING:Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].
10.1016/j.ebiom.2023.104503
Association of antihypertensive drugs with fracture and bone mineral density: A comprehensive drug-target Mendelian randomization study.
Frontiers in endocrinology
Background:Observational studies have investigated the associations between antihypertensive drugs and fracture risk as well as bone mineral density (BMD), but yielding controversial results. Methods:In this study, a comprehensive drug-target Mendelian randomization (MR) analysis was conducted to systematically examine the associations between genetic proxies for eight common antihypertensive drugs and three bone health-related traits (fracture, total body BMD [TB-BMD], and estimated heel BMD [eBMD]). The main analysis used the inverse-variance weighted (IVW) method to estimate the causal effect. Multiple MR methods were also employed to test the robustness of the results. Results:The genetic proxies for angiotensin receptor blockers (ARBs) were associated with a reduced risk of fracture (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.54 to 0.84; = 4.42 × 10; adjusted = 0.004), higher TB-BMD (β = 0.36, 95% CI: 0.11 to 0.61; = 0.005; adjusted = 0.022), and higher eBMD (β = 0.30, 95% CI: 0.21 to 0.38; = 3.59 × 10; adjusted = 6.55 × 10). Meanwhile, genetic proxies for calcium channel blockers (CCBs) were associated with an increased risk of fracture (OR = 1.07, 95% CI: 1.03 to 1.12; = 0.002; adjusted = 0.013). Genetic proxies for potassium sparing diuretics (PSDs) showed negative associations with TB-BMD (β = -0.61, 95% CI: -0.88 to -0.33; = 1.55 × 10; adjusted = 1.86 × 10). Genetic proxies for thiazide diuretics had positive associations with eBMD (β = 0.11, 95% CI: 0.03 to 0.18; = 0.006; adjusted = 0.022). No significant heterogeneity or pleiotropy was identified. The results were consistent across different MR methods. Conclusions:These findings suggest that genetic proxies for ARBs and thiazide diuretics may have a protective effect on bone health, while genetic proxies for CCBs and PSDs may have a negative effect.
10.3389/fendo.2023.1164387
Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization.
Frontiers in immunology
Objectives:Our aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods. Methods:We extracted summary statistics from the abundance of 211 microbiota taxa from the MiBioGen (N =18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N =7738), gout from the Global Biobank Meta-analysis Initiative (N =1,448,128), urate from CKDGen (N =288,649), and replication datasets from the Global Urate Genetics Consortium (N gout =69,374; N urate =110,347). We used linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) to detect genetic causality between microbiota and gout/urate. Mediation MR and colocalization were performed to investigate potential mediators in the association between microbiota and urate metabolism. Results:Two taxa had a common causal effect on both gout and urate, whereas the family was replicable. Six taxa were commonly affected by both gout and urate, whereas the genus was replicable. Genetic correlation supported significant results in MR. Two microbiota metabolic pathways were commonly affected by gout and urate. Mediation analysis indicated that the order and family had protective effects on urate mediated by increasing docosahexaenoic acid. These two bacteria shared a common causal variant rs182549 with both docosahexaenoic acid and urate, which was located within locus. Conclusions:Gut microbiota and host urate metabolism had a bidirectional causal association, implicating the critical role of host-microbiota crosstalk in hyperuricemic patients. Changes in gut microbiota can not only ameliorate host urate metabolism but also become a foreboding indicator of urate metabolic diseases.
10.3389/fimmu.2023.1148591
The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study.
EBioMedicine
BACKGROUND:Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. METHODS:We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). FINDINGS:We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG β = -0.934 (CI = [-2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477-1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = -1.3 ([-2.533 to -0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = -0.117 (95% CI [-1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. INTERPRETATION:In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. FUNDING:Wellcome (220740/Z/20/Z).
10.1016/j.ebiom.2023.104537
Causal effects of gut microbiota on the risk of chronic kidney disease: a Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Previous studies have reported that gut microbiota is associated with an increased risk of chronic kidney disease (CKD) progression. However, whether gut microbiota has a causal effect on the development of CKD has not been revealed. Thus, we aimed to analyze the potential causal effect of gut microbiota on the risk of CKD using mendelian randomization (MR) study. Materials and Methods:Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa (N = 18340) were identified as instrumental variables. Two-sample MR was performed to evaluate the causal effect of gut microbiota on CKD (N = 480698), including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot. Statistical powers were also calculated. Results:The genetically predicted higher abundance of order was causally associated with an increased risk of CKD (odds ratio = 1.15, 95% confidence interval: 1.05-1.26; = 0.0026). Besides, we also detected potential causalities between nine other taxa (, , , , , , , and ) and CKD ( < 0.05). No heterogeneity or pleiotropy was detected for significant estimates. Conclusion:We found that and nine other taxa are associated with CKD, thus confirming that gut microbiota plays an important role in the pathogenesis of CKD. Our work also provides new potential indicators and targets for screening and prevention of CKD.
10.3389/fcimb.2023.1142140
Associations between diet and incidence risk of lung cancer: A Mendelian randomization study.
Frontiers in nutrition
Background:Observational studies have revealed associations between diet and lung cancer. However, it is unclear whether the association is disturbed by confounding factors. We used a two-sample Mendelian randomization (MR) method to characterize the associations between diet and the lung cancer risk (including 3 subtypes: lung adenocarcinoma (LA), squamous cell lung carcinoma (SqCLC), and small cell lung cancer (SCLC)). Materials and methods:Data on 20 diets were screened from the UK Biobank. Lung cancer data came from a large meta-analysis of 85,716 individuals. The inverse-variance weighted method was used as the main analysis. Sensitivity analysis was also used to explain the different multiplicity patterns of the final model. Results:Our results showed significant evidence that 3 diets were associated with lung cancer [odds ratio (OR): 0.271, 95% confidence interval (CI): 0.150-0.488, = 1.46 × 10, dried fruit; OR: 3.010, 95% CI: 1.608-5.632, = 5.70 × 10, beer] and SqCLC (OR: 0.135, 95% CI: 0.062-0.293, = 2.33 × 10, dried fruit; OR: 0.485, 95% CI: 0.328-0.717, = 2.9 × 10, cheese). There were also suggestive correlations between 5 dietary intakes and lung cancer (OR: 0.441, 95% CI: 0.250-0.778, = 0.008, cereal; OR: 2.267, 95% CI: 1.126-4.564, = 0.022, beef), LA (OR: 0.494, 95% CI: 0.285-0.858, = 0.012, dried fruit; OR: 3.536, 95% CI: 1.546-8.085, = 0.003, beer) and SCLC (OR: 0.006, 95% CI: 0.000-0.222, = 0.039, non-oily fish; OR: 0.239, 95% CI: 0.086-0.664, = 0.006, dried fruit). No other association between diet and lung cancer was observed. Conclusion:Our study preliminary found that cheese, dried fruit, and beer intake were significantly associated with the risk of lung cancer or its subtypes, while cereal, beef, and non-oily fish intake were suggestively associated with the risk of lung cancer or its subtypes. Well-designed prospective studies are still needed to confirm our findings in the future.
10.3389/fnut.2023.1149317
Association between sleep traits and primary liver cancer: A Mendelian randomization analysis.
European journal of clinical investigation
BACKGROUND:Primary liver cancer (PLC) is the sixth most frequently occurring cancer, representing one of the top 5 leading causes of cancer-related mortality worldwide. Recently, researchers have focused more on the impact of living habits on the incidence and development of tumours. This study reports a relationship between sleep traits and PLC. METHODS:In this study, we used published genome-wide association studies to obtain exposure factors of 6 sleep traits. Mendelian randomization (MR) analysis was used to assess the causal relationship between sleep traits and PLC via inverse-variance weighted (IVW), MR Egger and weighted median. Sensitivity analysis was used to reduce the bias. RESULTS:Our investigation revealed that there was a negative correlation between sleep duration and the group of liver and bile duct cancer by IVW (p-value = .042), and this result was similarly observed in the liver cell carcinoma group by Weighted Median (p-value = .026). In contrast, there was a positive correlation found between napping during the day and primary liver cancer in the cohorts of liver and bile duct cancer (p-value = .030), liver cell carcinoma (p-value = .043) and malignant neoplasm of other and unspecified parts of the biliary tract (p-value = .016) by IVW. Furthermore, our study also revealed a positive correlation between insomnia and malignant neoplasm of the liver and intrahepatic bile ducts by IVW (p-value = .022). CONCLUSIONS:Overall, our study indicates that insomnia and nap during the day may be risk factors of PLC and adequate night sleep might keep us away from PLC.
10.1111/eci.14002
Genetically Predicted Body Selenium Concentration and estimated GFR: A Mendelian Randomization Study.
Kidney international reports
Introduction:Selenium is a trace mineral that is commonly included in micronutrient supplements. The effect of selenium on kidney function remains unclear. A genetically predicted micronutrient and its association with estimated glomerular filtration rate (eGFR) can be used to assess the causal estimates by Mendelian randomization (MR). Methods:In this MR study, we instrumented 11 genetic variants associated with blood or total selenium levels from a previous genome-wide association study (GWAS). The association between genetically predicted selenium concentration and eGFR was first assessed by summary-level MR in the chronic kidney disease(CKDGen) GWAS meta-analysis summary statistics, including 567,460 European samples. Inverse-variance weighted and pleiotropy-robust MR analyses were performed, in addition to multivariable MR adjusted for the effects of type 2 diabetes mellitus. Replication analysis was performed with individual-level UK Biobank data, including 337,318 White individuals of British ancestry. Results:Summary-level MR analysis indicated that a genetically predicted 1 SD increase in selenium concentration was significantly associated with lower eGFR (-1.05 [-1.28, -0.82] %). The results were similarly reproduced by pleiotropy-robust MR analysis, including MR-Egger and weighted-median methods, and consistent even in the multivariable MR adjusted for diabetes. In the UK Biobank data, genetically predicted higher selenium concentration was also significantly associated with lower eGFR (- 0.36 [-0.52, -0.20] %), and the results were similar when body mass index, waist circumference, hypertension, and diabetes mellitus covariates were adjusted (-0.33 [-0.50, -0.17] %). Conclusion:This MR study supports the hypothesis that higher genetically predicted body selenium is causally associated with lower eGFR.
10.1016/j.ekir.2023.01.009
Sleep Duration and Visceral Adipose Tissue: Linear and Nonlinear Mendelian Randomization Analyses.
The Journal of clinical endocrinology and metabolism
CONTEXT:Increasing evidence suggests that sleep is important for fat metabolism. However, the causal relationship between sleep duration and visceral adipose tissue (VAT) needs to be further clarified. OBJECTIVE:This study investigated the linear and nonlinear causal association between sleep duration and VAT. METHODS:This study used one-sample and two-sample Mendelian randomization MR). Single-nucleotide polymorphisms (SNPs) associated with sleep duration at genome-wide significance were obtained from published genome-wide association studies. We also recalculated the correlation between each SNP and sleep duration in the UK Biobank. The associations of SNPs with predicted VAT (396 858 participants) were conducted in the UK Biobank. RESULTS:A total of 396 858 eligible participants (54.10% females, 57 ± 8 years old) were included in the study. The participants slept 7.17 ± 1.04 hours and stored 1.25 ± 0.88 kg of VAT on average. Genetically predicted sleep duration was significantly associated with VAT. For each 1-hour increase in genetically predicted sleep duration, the reduction in predicted VAT mass was 0.11 kg (P = 8.18E-16) in total, 0.17 kg (P = 3.30E-11) in men and 0.07 kg (P = 1.94E-06) in women. Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and VAT in all participants, men, and women. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the increased VAT. In contrast, no clear evidence on the causal effect of genetically predicted long sleep duration on VAT mass was found. CONCLUSION:The causal association of sleep duration with VAT was L-type. Our findings support that short sleep duration is a risk factor for increasing VAT, thus reinforcing the probability that increasing sleep duration may decrease VAT.
10.1210/clinem/dgac551
Mendelian Randomization Indicates a Causal Role for Omega-3 Fatty Acids in Inflammatory Bowel Disease.
International journal of molecular sciences
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal system. Omega-3 (ω) fatty acids are polyunsaturated fatty acids (PUFAs) that are largely obtained from diet and have been speculated to decrease the inflammatory response that is involved in IBD; however, the causality of this association has not been established. A two-sample Mendelian randomization (MR) was used to assess genetic associations between 249 circulating metabolites measured in the UK Biobank as exposures and IBD as the outcome. The genome-wide association study summary level data for metabolite measurements and IBD were derived from large European ancestry cohorts. We observed ω fatty acids as a significant protective association with IBD, with multiple modes of MR evidence replicated in three IBD summary genetic datasets. The instrumental variables that were involved in the causal association of ω fatty acids with IBD highlighted an intronic SNP, rs174564, in , a protein engaged in the first step of alpha-linolenic acid desaturation leading to anti-inflammatory EPA and thence DHA production. A low ratio of ω to ω fatty acids was observed to be a causal risk factor, particularly for Crohn's disease. ω fatty acid supplementation may provide anti-inflammatory responses that are required to attenuate inflammation that is involved in IBD.
10.3390/ijms232214380
Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization.
Neurology
BACKGROUND AND OBJECTIVES:Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS:We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS:Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15-1.19; = 2.1 × 10), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; = 8.6 × 10), psoriasis (HR 1.13; 95% CI 1.10-1.16; = 2.6 × 10), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; = 4.0 × 10), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; = 2.8 × 10) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [OR] 1.23; 95% CI 1.06-1.42; = 0.007) and lower risk of Crohn disease (OR 0.73; 95% CI -0.62 to 0.86; = 1.3 × 10). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk. DISCUSSION:Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.
10.1212/WNL.0000000000201489
Genetic Predisposition of Both Waist Circumference and Hip Circumference Increased the Risk of Venous Thromboembolism.
Thrombosis and haemostasis
BACKGROUND: Obesity, especially abdominal obesity, is an independent indicator of increased cardiovascular risk. Observational studies have shown an observational association between obesity and venous thromboembolism (VTE). As a type of VTE, pulmonary embolism (PE) is also associated with obesity. However, it is unclear whether the observed associations are causal or caused by confounding bias or reverse causality. METHODS: We performed a two-sample test by obtaining the exposure dataset of waist circumference (WC) and hip circumference (HC) from the Neale Laboratory Consortium's genome-wide association study summary data and the summary-level outcome data of VTE and PE from FinnGen Biobank of European ancestry to determine the causal effect of WC and HC on VTE and PE. RESULTS: All three Mendelian randomization methods displayed a positive association between WC/HC and VTE/PE. WC and HC were positively associated with VTE (odds ratio [OR] = 1.803 per 1 standard deviation [SD] increase in WC, 95% confidence interval [CI] = 1.393-2.333; < 0.001; OR = 1.479 per 1 SD increase in HC, 95% CI = 1.219-1.796; < 0.001, respectively). Furthermore, we found a causal association between genetically predicted WC/HC and a higher risk of PE (OR = 1.929 per 1 SD increase in WC, 95% CI = 1.339-2.778, < 0.001; OR = 1.431 per 1 SD increase in HC, 95% CI =1.095-1.869; = 0.009, respectively). CONCLUSION: There is a significant causal relationship between WC/HC and VTE/PE, which is consistent with observational studies. Taking measures to reduce WC/HC of obesity may help reduce the incidence of VTE/PE.
10.1055/a-1980-8852
Effect of blood lipids and lipid-lowering therapies on osteoarthritis risk: A Mendelian randomization study.
Frontiers in medicine
Background:We aimed to investigate the effects of blood lipids and lipid-lowering agents on osteoarthritis (OA) risk. Materials and methods:We performed Mendelian randomization (MR) analyses to estimate the causal effect of blood low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels on knee and hip OA. Single nucleotide polymorphisms (SNPs) were selected from large genome-wide association studies (GWASs) of individuals of European ancestry as genetic instruments for blood lipid levels. The associations of selected genetic instruments with knee and hip OA were estimated in a recent GWAS of the UK Biobank and arcOGEN datasets. Univariate and multivariate MR analyses were performed to detect and adjust for potential pleiotropy. Furthermore, genetic instruments in , and regions were used to mimic LDL-C-lowering effects of statin, ezetimibe, and evolocumab, respectively. Results:Genetically determined LDL-C increments led to reduced risks of both knee OA (OR = 0.91 per 1-SD increment, 95% CI: 0.86-0.95, = 6.3 × 10) and hip OA (OR = 0.92, 95% CI: 0.85-0.99, = 0.027). Multivariate MR analysis proved that the effect was independent of HDL-C, TG, and body mass index. TG increment was associated with reduced risks of hip OA in the univariate MR analysis; however, this was not supported by the multivariate MR analysis. Genetically proxied LDL-C-lowering effects of statins are related to increased risks of knee OA but not hip OA. Conclusions:The findings suggested that LDL-C increments have independent protective effects on both knee and hip OA. LDL-C-lowering effects of statins may increase the risk of knee OA.
10.3389/fmed.2022.990569
Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study.
Hypertension (Dallas, Tex. : 1979)
BACKGROUND:Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. METHODS:Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. RESULTS:Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40-0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education; 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. CONCLUSIONS:Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.
10.1161/HYPERTENSIONAHA.122.20286
Association between homocysteine and nonalcoholic fatty liver disease: Mendelian randomisation study.
European journal of clinical investigation
BACKGROUND:Many observational studies explore the relationship between homocysteine (Hcy) and nonalcoholic fatty liver disease (NAFLD), whereas the causality of this association remains uncertain, especially in European populations. We performed a bidirectional Mendelian randomisation study to elucidate the causal association between Hcy and NAFLD. Furthermore, we explored the relationship of Hcy with liver enzymes, including alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). METHODS:Two-sample Mendelian randomisation study was conducted. Summary statistics for Hcy were obtained from a genome-wide association studies (GWAS) meta-analysis comprising 44,147 subjects. Summary-level data for NAFLD were acquired from a GWAS meta-analysis of 8434 cases and 770,180 noncases and another GWAS meta-analysis of 1483 cases and 17,781 noncases. Summary-level data for three liver enzymes were available from the UK Biobank. RESULTS:Genetic associations of Hcy concentrations with NAFLD and liver enzymes were observed. Genetically predicted higher Hcy concentrations were consistently associated with an increased NAFLD risk in two data sources. The combined odds ratio of NAFLD was 1.25 (95% confidence interval [CI], 1.05-1.45) per SD increase in Hcy concentrations. Genetically predicted higher Hcy concentrations showed significant association with ALP (Beta .69; 95% CI, 0.04-1.34), ALT (Beta 0.56; 95% CI, 0.15-0.97) and AST levels (Beta .57; 95% CI, 0.10-1.04). Genetic liability to NAFLD was not associated with Hcy concentrations. CONCLUSIONS:This study has clinical implications as it indicates that increased Hcy concentrations increase the relevant liver enzymes and may play a role in NAFLD risk in European populations.
10.1111/eci.13895
Milk consumption and risk of twelve cancers: A large-scale observational and Mendelian randomisation study.
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Milk consumption is a modifiable lifestyle factor that has been associated with several cancer types in observational studies. Limited evidence exists regarding the causality of these relationships. Using a genetic variant (rs4988235) near the lactase gene (LCT) locus that proxies milk consumption, we conducted a comprehensive survey to assess potential causal relationships between milk consumption and 12 types of cancer. METHODS:Our analyses were conducted using white British participants of the UK Biobank (n = up to 255,196), the FinnGen cohort (up to 260,405), and available cancer consortia. We included cancers with previous evidence of an association with milk consumption in observational studies, as well as cancers common in both UK Biobank and FinnGen populations (>1000 cases). We evaluated phenotypic associations of milk intake and cancer incidence in the UK Biobank, and then used a Mendelian randomisation (MR) approach to assess causality in the UK Biobank, FinnGen consortium, and combined analyses incorporating additional consortia data for five cancers. In MR meta-analyses, case numbers for cancers of breast, ovary, uterus, cervix, prostate, bladder and urinary tract, colorectum, and lung ranged between 6000 and 148,000 cases, and between 780 and 1342 cases for cancers of the liver, mouth, stomach and diffuse large B-cell lymphoma. RESULTS:In observational analyses, milk consumption was associated with higher risk of bladder and urinary tract cancer (OR 1.23, 95% CI 1.03-1.47), but not with any other cancer. This association was not confirmed in the MR analysis, and genetically predicted milk consumption showed a significant association only with lower risk of colorectal cancer (0.89, 0.81-0.98 per additional 50 g/day). In the MR analyses conducted among individual cohorts, genetically predicted milk consumption provided evidence for an association with lower colorectal cancer in the FinnGen cohort (0.85, 0.74-0.97), and in the UK Biobank greater risk of female breast cancer (1.12, 1.03-1.23), and uterine cancer in pre-menopausal females (3.98, 1.48-10.7). CONCLUSION:In a comprehensive survey of milk-cancer associations, we confirm of a protective role of milk consumption for colorectal cancer. Our analyses also provide some suggestion for higher risks of breast cancer and premenopausal uterine cancer, warranting further investigation.
10.1016/j.clnu.2022.11.006
Kidney function and risk of dementia: Observational study, meta-analysis, and two-sample mendelian randomization study.
European journal of epidemiology
Whether impaired kidney function is associated with increased risk of developing dementia is unclear. We investigated the association between estimated glomerular filtration rate (eGFR) and dementia. Using a triangulation approach, we performed (1) a prospective study in 90,369 Danes from the Copenhagen General Population Study (CGPS), (2) a meta-analysis in 468,699 Scandinavians (including CGPS) and (3) a two-sample Mendelian randomization study in 218,792-1,004,040 Europeans using summary data from largest publicly available genome wide association studies (GWASs). During up to 15 years of follow-up (CGPS), 2,468 individuals developed dementia. Age and sex standardized percentile of eGFR below versus above the median conferred a multifactorially adjusted hazard ratio of 1.09 (95% confidence interval: 1.01-1.18). In meta-analysis, random-effects risk of dementia was 1.14 (1.06-1.22) for mildly decreased eGFR (60-90 mL/min/1.73 m), 1.31 (0.92-1.87) for moderately decreased eGFR (30-59 mL/min/1.73 m) and 1.91 (1.21-3.01) for severely decreased eGFR (< 30 mL/min/1.73 m), compared to reference eGFR (> 90 mL/min/1.73 m). Using directly comparable eGFR measures (log[eGFR] scaled to one standard deviation, as well as eGFR below versus above 60 mL/min/1.73 m), we found no association with risk of dementia in observational CGPS or in Mendelian randomization analyses. In conclusion, impaired kidney function was associated with modestly increased risk of developing dementia. This was not supported by causal, genetic analyses using a Mendelian randomization approach. However, future stronger genetic instruments for kidney function and larger GWASs with more dementia cases, particularly for the vascular dementia subtype, warrant a re-evaluation of the causal hypothesis.
10.1007/s10654-022-00923-z
Physical activity, sedentary behavior, and the risk of type 2 diabetes: A two-sample Mendelian Randomization analysis in the European population.
Frontiers in endocrinology
Physical activity (PA) and sedentary behaviors (SB) have been linked to the risk of type 2 diabetes (T2DM) in observational studies; however, it is unclear whether these associations are causative or confounded. This study intends to use summary genetic data from the UK Biobank and other consortiums in conjunction with the two-sample Mendelian Randomization (MR) approach to solve this problem. The inverse variance weighted (IVW) technique was utilized as the primary analysis, with sensitivity analyses using the MR-Egger, weighted-median, and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) techniques. Inverse associations between self-reported moderate PA (OR: 0.3096, 95% CI: 0.1782-0.5380) and vigorous PA (OR: 0.2747, 95% CI: 0.1390-0.5428) with T2DM risk were found, respectively. However, accelerometer-based PA measurement (average acceleration) was not associated with T2DM risk (OR: 1.0284, 95% CI: 0.9831-1.0758). The time (hours/day) spent watching TV was associated with T2DM risk (OR: 2.3490, 95% CI: 1.9084-2.8915), while the time (hours/day) spent using the computer (OR: 0.8496, 95% CI: 0.7178-1.0056), and driving (OR: 3.0679, 95% CI: 0.8448-11.1415) were not associated with T2DM risk. The sensitivity analysis revealed relationships of a similar magnitude. Our study revealed that more PA and less TV viewing were related to a decreased T2DM risk, and provided genetic support for a causal relationship between PA, TV viewing, and T2DM risk.
10.3389/fendo.2022.964132
Vitamin D Levels and Risk of Juvenile Idiopathic Arthritis: A Mendelian Randomization Study.
Arthritis care & research
OBJECTIVES:Observational studies report mixed findings regarding the association between vitamin D and juvenile idiopathic arthritis (JIA) incidence or activity; however, such studies are susceptible to considerable bias. Because low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation, we examined the causal effect of the major circulating form of vitamin D, 25-hydroxy vitamin D (25-[OH]D), on JIA incidence using Mendelian randomization (MR). METHODS:In this 2-sample MR analysis, we used summary level data from the largest and most recent genome-wide association study of 25-(OH)D levels (sample size 443,734), alongside summary data from 2 JIA genetic studies (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy, we employed multiple MR methods and sensitivity analyses. RESULTS:We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (odds ratio 1.00 [95% confidence interval (95% CI) 0.76, 1.33] per SD increase in standardized natural-log transformed 25-[OH]D levels). This estimate was consistent across all methods tested. Additionally, there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 SD change in standardized natural-log transformed 25-[OH]D levels per doubling odds in genetically predicted JIA [95% CI -0.006, 0.002]). CONCLUSION:Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.
10.1002/acr.24815
Genetic support of a causal relationship between cannabis use and educational attainment: a two-sample Mendelian randomization study of European ancestry.
Addiction (Abingdon, England)
BACKGROUND AND AIMS:Excessive cannabis use may lead to lower educational attainment. However, this association may be due to confounders and reverse causality. We tested the potential causal relationship between cannabis use disorder (CUD) or life-time cannabis use (LCU) and educational attainment. DESIGN:Bidirectional two-sample Mendelian randomization (MR) study was conducted. Our primary method was inverse-variance weighted (IVW) MR, with a series of sensitivity analyses. Multivariable MR (MVMR) was performed to estimate any direct effect independent of intelligence, smoking initiation or attention deficit hyperactivity disorder (ADHD). SETTING AND PARTICIPANTS:European ancestry individuals. The sample sizes of the genome-wide association study ranged from 55 374 to 632 802 participants. MEASUREMENTS:Genetic variants of CUD, LCU or educational attainment. FINDINGS:Using univariable MR, we found evidence of a potential causal effect of genetic liability to CUD on a lower educational attainment [MR, 95% confidence interval (CI) = -1.2 month (-1.9 month, -0.5 month); P = 0.0008]. However, we found no evidence of an effect of genetic liability to LCU on educational attainment [MR, 95% CI = 0.5 month (-1.5 month, 2.6 month), P = 0.6032]. Reverse direction analysis suggested that genetic liability to higher educational attainment had a potential causal effect on lower risk of CUD [odds ratio (OR), 95% CI = 0.39 (0.29, 0.52), P = 1.69 × 10 ]. We also found evidence of potential causal effect from genetic liability to higher educational attainment to higher risk of LCU [OR, 95% CI = 1.35 (1.11, 1.66), P = 0.0033]. CONCLUSIONS:Genetic liability to cannabis use disorder may lead to lower educational attainment. Genetic liability to higher educational attainment may also lead to higher life-time cannabis use risk and lower cannabis use disorder risk. However, the bidirectional effect between cannabis use disorder and educational attainment may be due to shared risk factors (e.g. attention-deficit hyperactivity disorder).
10.1111/add.16090
Mendelian Randomization Implicates Bidirectional Association between Myopia and Primary Open-Angle Glaucoma or Intraocular Pressure.
Ophthalmology
PURPOSE:Observational studies suggest that myopic eyes carry a greater risk of primary open-angle glaucoma (POAG); however, the evidence for this association is inconsistent. This may be the result of confounding factors that arise from myopia that complicate clinical tests for glaucoma. This study used Mendelian randomization (MR) analysis to determine genetic causal associations among myopia, glaucoma, and glaucoma-related traits that overcome the effects of external confounders. DESIGN:Bidirectional genetic associations between myopia and refractive spherical equivalent (RSE), POAG, and POAG endophenotypes were investigated. PARTICIPANTS:Data from the largest publicly available genetic banks (n = 216,257-542,934) were analyzed. METHODS:Multiple MR models and multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG. MAIN OUTCOME MEASURES:Genetic causal associations between myopia and POAG and POAG endophenotypes. RESULTS:We found consistent bidirectional genetic associations between myopia and POAG and between myopia and intraocular pressure (IOP) using multiple MR models at Bonferroni-corrected levels of significance. Intraocular pressure showed the most significant mediation effect on RSE and POAG (Sobel test, 0.13; 95% confidence interval, 0.09-0.17; P = 1.37 × 10). CONCLUSIONS:A strong bidirectional genetic causal link exists between myopia and POAG that is mediated mainly by IOP. Our findings suggest that IOP-lowering treatment for glaucoma may be beneficial in myopic eyes, despite the challenges of establishing a clear clinical diagnosis. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.
10.1016/j.ophtha.2022.11.030
Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.
Genetics in medicine : official journal of the American College of Medical Genetics
PURPOSE:The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon. METHODS:We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure. RESULTS:Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain. CONCLUSIONS:Bayesian penetrance estimates provide a continuous framework for variant interpretation.
10.1016/j.gim.2022.12.002
Evaluating the causal effect of tobacco smoking on white matter brain aging: a two-sample Mendelian randomization analysis in UK Biobank.
Addiction (Abingdon, England)
BACKGROUND AND AIMS:Tobacco smoking is a risk factor for impaired brain function, but its causal effect on white matter brain aging remains unclear. This study aimed to measure the causal effect of tobacco smoking on white matter brain aging. DESIGN:Mendelian randomization (MR) analysis using two non-overlapping data sets (with and without neuroimaging data) from UK Biobank (UKB). The group exposed to smoking and control group consisted of current smokers and never smokers, respectively. Our main method was generalized weighted linear regression with other methods also included as sensitivity analysis. SETTING:United Kingdom. PARTICIPANTS:The study cohort included 23 624 subjects [10 665 males and 12 959 females with a mean age of 54.18 years, 95% confidence interval (CI) = 54.08, 54.28]. MEASUREMENTS:Genetic variants were selected as instrumental variables under the MR analysis assumptions: (1) associated with the exposure; (2) influenced outcome only via exposure; and (3) not associated with confounders. The exposure smoking status (current versus never smokers) was measured by questionnaires at the initial visit (2006-10). The other exposure, cigarettes per day (CPD), measured the average number of cigarettes smoked per day for current tobacco users over the life-time. The outcome was the 'brain age gap' (BAG), the difference between predicted brain age and chronological age, computed by training machine learning model on a non-overlapping set of never smokers. FINDINGS:The estimated BAG had a mean of 0.10 (95% CI = 0.06, 0.14) years. The MR analysis showed evidence of positive causal effect of smoking behaviors on BAG: the effect of smoking is 0.21 (in years, 95% CI = 6.5 × 10 , 0.41; P-value = 0.04), and the effect of CPD is 0.16 year/cigarette (UKB: 95% CI = 0.06, 0.26; P-value = 1.3 × 10 ; GSCAN: 95% CI = 0.02, 0.31; P-value = 0.03). The sensitivity analyses showed consistent results. CONCLUSIONS:There appears to be a significant causal effect of smoking on the brain age gap, which suggests that smoking prevention can be an effective intervention for accelerated brain aging and the age-related decline in cognitive function.
10.1111/add.16088
Bidirectional associations between eosinophils, basophils, and lymphocytes with atopic dermatitis: A multivariable Mendelian randomization study.
Frontiers in immunology
Background:Despite being prone to reverse causation and having unmeasured confounding factors, many clinical observational studies have highlighted the critical association between basophils, eosinophils, and lymphocytes and atopic dermatitis (AD). Whether these cells play a causal role in AD development remains uncertain. Methods:Data were obtained from the UK Biobank and the Blood Cell Consortium, from a large publicly available genome-wide association study (GWAS) with more than 500,000 subjects of European ancestry and for AD from three independent cohorts with more than 700,000 subjects of European ancestry. We performed single-variable Mendelian randomization (SVMR), followed by multivariable Mendelian randomization (MVMR) to assess the total and direct effects of immune cell counts on AD risk. Results:SVMR estimates showed that genetically predicted higher eosinophil [odds ratio (OR): 1.23, 95% confidence interval (CI): 1.17-1.29, = 5.85E-16] and basophil counts (OR: 1.11, 95% CI: 1.03-1.19, = 0.004) had an adverse effect on the risk of AD, while a higher lymphocyte count (OR: 0.93, 95% CI: 0.89-0.98, = 0.006) decreased the risk. Reverse MR analysis showed higher basophil (beta: 0.04, 95% CI: 0.01-0.07, = 0.014) and lower lymphocyte counts (beta: -0.05, 95% CI: -0.09 to -0.01, = 0.021) in patients with AD. In MVMR, the effects of eosinophils (OR: 1.19, 95% CI: 1.09-1.29, = 8.98E-05), basophils (OR: 1.19, 95% CI: 1.14-1.24, = 3.72E-15), and lymphocytes (OR: 0.93, 95% CI: 0.89-0.98, = 0.006) were still significant. Discussion:Mendelian randomization (MR) findings suggest that an increase in the eosinophil and basophil counts and a decrease in the lymphocyte counts are potential causal risk factors for AD. These risk factors are independent of each other.
10.3389/fimmu.2022.1001911
Causal Effect of Blood Pressure on Bone Mineral Density and Fracture: A Mendelian Randomization Study.
Frontiers in endocrinology
Background:Hypertension may have some association with osteoporosis. This Mendelian randomization (MR) study aimed to explore the causal effect of blood pressure (BP) on bone mineral density (BMD), fall, and fracture. Methods:We used the genome-wide association study (GWAS) summary data among 330,956 European-descent individuals to identify 107 single-nucleotide polymorphisms (SNPs) as the instrumental variables of BP. MR analyses of these instruments were performed on 53,236 European individuals for the association with forearm BMD (FA-BMD), femoral neck BMD (FN-BMD), and lumbar spine BMD (LS-BMD); 451,179 European individuals for fall susceptibility; and up to 1.2 million individuals from European descent for fracture. Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of BP on different outcomes, while weighted median, MR-egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses. Results:Genetically high pulse pressure (PP) could significantly improve FA-BMD (beta-estimate: 0.038, 95% confidence interval [CI]: 0.013 to 0.063, SE:0.013, P-value=0.003<Bonferroni correction P) in the IVW analysis, indicating that 1-SD increase in PP was associated with the improvement in FA-BMD levels by 0.038 g/cm (95% CI: 0.013 to 0.063). This positive finding was also confirmed by weighted-median analysis (beta-estimate: 0.034, 95% CI: 0.000 to 0.067, SE:0.017, P-value=0.046) and MR-Egger analysis (beta-estimate: 0.117, 95% CI: 0.026 to 0.208, SE:0.046, P-value=0.011). However, there was no remarkable MR association between BP and other outcomes (i.e., FN-BMD, LS-BMD, fall, and fracture). Conclusions:Our findings reveal a potentially causal relationship between high PP and improved FA-BMD, which may provide new sights for the treatment of osteoporosis.
10.3389/fendo.2021.716681
The genetic etiology of periodic limb movement in sleep.
Sleep
STUDY OBJECTIVES:Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects. METHODS:The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization. RESULTS:We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, β = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, β = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS. CONCLUSIONS:Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.
10.1093/sleep/zsac121
Classical risk factors for primary coronary artery disease from an aging perspective through Mendelian Randomization.
GeroScience
The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.
10.1007/s11357-021-00498-9
Association of Circulating Branched-Chain Amino Acids with Cardiovascular Diseases: A Mendelian Randomization Study.
Nutrients
BACKGROUND:There have been reports linking branched-chain amino acids (BCAAs) to the hazard of various cardiovascular diseases (CVDs); however, the causal role of this relationship is still unclear. We conducted a study using bi-directional two-sample Mendelian randomization (MR) with the aim of investigating the possible causal correlation between BCAAs and 13 types of cardiovascular diseases. METHODS:The study analyzed data of the largest genome-wide association studies (GWAS) published for the total BCAAs, encompassing isoleucine, leucine, and valine, which were obtained from the UK Biobank, as well as data for 13 cardiovascular endpoints from the MRC-IEU, the FinnGen consortium, and the EBI database. The approach of the primary dissection used became the inverse-variance-weighted (IVW) approach, with additional analyses using the MR-PRESSO global test as well as MR-Egger regression with a view to determining horizontal pleiotropy. Heterogeneity was evaluated by means of Cochran's Q test. The study also conducted logistic regression dissection for the sake of investigating the correlation between cardiovascular events and serum BCAAs in the UK biobank cohort study. RESULTS:In this study, it was found that individuals with a genetic predisposition to more elevated levels for circulating total BCAAs had a higher hazard of peripheral arterial disease (OR 1.400, 95% CI 1.063, 1.844; = 0.017) in addition to stroke (OR 1.266, 95% CI 1.012, 1.585; = 0.039); circulating valine casually increased the risk of intracerebral hemorrhage (OR 1.760, 95% CI 1.116, 2.776; = 0.015), along with stroke (OR 1.269, 95% CI 1.079, 1.492; = 0.004); genetically predicted isoleucine showed a positive association with peripheral arterial disease (OR 1.466, 95% CI 1.044, 2.058; = 0.027), along with cardioembolic stroke (OR 1.547, 95% CI 1.126, 2.124; = 0.007); furthermore, leucine causally associated with stroke (OR 1.310, 95% CI 1.031, 1.663, = 0.027). In the UK Biobank cohort study, we detected that total BCAAs (OR: 1.285; 95% CI: 1.009, 1.636), valine (OR: 1.287; 95% CI: 1.009, 1.642), and isoleucine (OR: 1.352; 95% CI: 1.064, 1.718) were independently linked to stroke, but not leucine (OR: 1.146; 95% CI: 0.901, 1.458). No such association was found for BCAAs with peripheral arterial disease and intracerebral hemorrhage in the cohort study. CONCLUSIONS:In summary, circulating total BCAAs and valine may be causally associated with stroke. The association of BCAAs with other CVD events needs further study.
10.3390/nu15071580
Causal Associations Between Age at Diagnosis of Diabetes and Cardiovascular Outcomes: A Mendelian Randomization Study.
The Journal of clinical endocrinology and metabolism
CONTEXT:Whether diabetes diagnosed at different age groups is causally associated with cardiovascular diseases (CVDs) is unknown. OBJECTIVE:We conducted 2-sample Mendelian randomization analyses to investigate the causal associations of diabetes by age at diagnosis with 5 type-specific CVDs and 11 cardiometabolic traits. METHODS:We selected 208 single nucleotide polymorphisms (SNPs) for diabetes and 3, 21, 57, and 14 SNPs for diabetes diagnosed at <50, 50-60, 60-70, and >70 years, respectively, based on the genome-wide association study (GWASs) (24 986 cases/187 130 controls) in the UK Biobank, and extracted genetic associations with stroke, myocardial infarction, heart failure, atrial fibrillation, and CVD mortality, as well as blood pressures, adiposity measurements, and lipids and apolipoproteins from corresponding European-descent GWASs. The inverse variance-weighted method was used as the main analysis with several sensitivity analyses. RESULTS:Diabetes diagnosed at all 4 age groups was causally associated with increased risks of stroke (5-8%) and myocardial infarction (8-10%), higher systolic blood pressure (0.56-0.94 mmHg) and waist to hip ratio (0.003-0.004), and lower body mass index (0.31-0.42 kg/m2), waist circumference (0.68-0.99 cm), and hip circumference (0.57-0.80 cm). Diabetes diagnosed at specific age groups was causally associated with increased risks of heart failure (4%) and CVD mortality (8%), higher diastolic blood pressure (0.20 mmHg) and triglycerides (0.06 SD), and lower high-density lipoprotein cholesterol (0.02 mmol/L). The effect sizes of genetically determined diabetes on CVD subtypes and cardiometabolic traits were comparable and the corresponding 95% confidence intervals largely overlapped across the 4 age groups. CONCLUSION:Our findings provide novel evidence that genetically determined diabetes subgroups by age at diagnosis have similar causal effects on CVD and cardiometabolic risks.
10.1210/clinem/dgac658
Repurposing antidiabetic drugs for rheumatoid arthritis: results from a two-sample Mendelian randomization study.
European journal of epidemiology
Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20-0.73). Corresponding ORs (95%CIs) were 0.83 (0.44-1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.
10.1007/s10654-023-01000-9
Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans.
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. METHODS:We conducted race-conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan-Meier analysis, and log-rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. RESULTS:We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65-0.91, p-value = 0.0022), but not in the non-Hispanic EAs (HR = 0.97, 95% CI: 0.89-1.05, p-value = 0.4110). Sensitivity and sex-/age-stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome-wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA-specific beneficial effects of telmisartan for AD. DISCUSSION:Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. HIGHLIGHTS:Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR-γ agonistic properties with beneficial anti-diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.
10.1002/alz.12819
Associations of Homocysteine, Folate, and Vitamin B12 with Osteoarthritis: A Mendelian Randomization Study.
Nutrients
Homocysteine, inversely related to folate and vitamin B12, is an independent risk factor for several age-related disorders. However, little is known about the association of homocysteine and related vitamins with osteoarthritis (OA). This study aimed to elucidate the potential causal effects of homocysteine, folate, and vitamin B12 on site- and gender-specific OA by applying the two-sample Mendelian randomization (MR) approach. Genetically predicted homocysteine showed adverse effects on overall OA (95% confidence interval (CI): 1.044-1.155), knee OA (95% CI: 1.000-1.167), hip OA (95% CI: 1.057-1.297), and spine OA (95% CI: 1.017-1.216). Genetically predicted folate showed protective effects on overall OA (95% CI: 0.783-0.961) and spine OA (95% CI: 0.609-0.954). Folate (95% CI: 0.887-1.004) and vitamin B12 (95% CI: 0.886-1.009) showed a protective trend against knee OA. The patterns of associations were site and gender specific. In conclusion, homocysteine had adverse effects on OA, especially on OA at weight-bearing joints and in females. Folate and vitamin B12 had protective effects on OA. Homocysteine-lowering interventions may be a potential option in the treatment and prevention of OA.
10.3390/nu15071636
Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study.
Thrombosis journal
BACKGROUND:Experimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes. METHODS:A total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes. RESULTS:Genetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01-1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02-1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03-1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings. CONCLUSIONS:We found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.
10.1186/s12959-023-00485-4
Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects.
Molecular psychiatry
Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.
10.1038/s41380-022-01690-9
Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.
The American journal of clinical nutrition
BACKGROUND:The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES:To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS:Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS:Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS:These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
10.1093/ajcn/nqab003
Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
European heart journal
AIMS:Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS:A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION:Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
10.1093/eurheartj/ehad142
Genetically predicted green tea intake and the risk of arterial embolism and thrombosis.
Frontiers in medicine
Background:In previous observational studies, green tea intake has been demonstrated to protect against arterial embolism and thrombosis. However, whether there is a causative connection between green tea intake and arterial embolism and thrombosis is currently unclear. Methods:A two-sample Mendelian randomization (MR) study has been designed to explore whether there is a causal association between green tea intake and arterial embolism and thrombosis by acquiring exposure and outcome data from previously published research. Data from the MRC-IEU (data on green tea intake, 64,949 participants) consortium and the FinnGen project (data on arterial embolism and thrombosis, 278 cases of arterial thrombosis and 92,349 control participants) has been utilized to determine the causal impact of green tea intake on arterial embolism and thrombosis. Results:We found that genetically predicted green tea intake was causally associated with a lower risk of arterial embolism and thrombosis (IVW odds ratio [OR] per SD decrease in green tea intake = 0.92 [95% confidence interval, 0.85-0.99]; = 0.032). Moreover, the sensitivity analysis (both MR Egger regression and weighted median) yielded comparable estimates but with low precision. No directional pleiotropic effect between green tea intake and arterial embolism and thrombosis was observed in both funnel plots and MR-Egger intercepts. Conclusions:Our study provided causal evidence that genetically predicted green tea intake may be a protective factor against arterial embolism and thrombosis.
10.3389/fmed.2023.1156254
Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.
PLoS medicine
BACKGROUND:Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS:We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS:In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.
10.1371/journal.pmed.1003897
Investigating the potential anti-depressive mechanisms of statins: a transcriptomic and Mendelian randomization analysis.
Translational psychiatry
Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains unclear whether statins have any beneficial effects on depression, and if so, what the underlying molecular mechanisms are. Here, we aimed to use genomic approaches to investigate this further. Using Connectivity Map (CMap), we first investigated whether statins and antidepressants shared pharmacological effects by interrogating gene expression responses to drug exposure in human cell lines. Second, using Mendelian randomization analysis, we investigated both on-target (through HMGCR inhibition) and potential off-target (through ITGAL and HDAC2 inhibition) causal effects of statins on depression risk and depressive symptoms, and traits related to the shared biological pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins in HA1E cells (indicated by an average connectivity score with statins > 90) were found to be enriched for antidepressants (12 out of 38 antidepressants; p = 9E-08). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for diverse cellular and metabolic pathways, and various immune activation, development and response processes. MR analysis did not identify any significant associations between statin exposure and depression risk or symptoms after multiple testing correction. However, genetically proxied HMGCR inhibition was strongly associated with alterations in platelets (a prominent serotonin reservoir) and monocyte percentage, which have previously been implicated in depression. Genetically proxied ITGAL inhibition was strongly associated with basophil, monocyte and neutrophil counts. We identified biological pathways that are commonly perturbed by both statins and antidepressants, and haematological biomarkers genetically associated with statin targets. Our findings warrant pre-clinical investigation of the causal role of these shared pathways in depression and potential as therapeutic targets, and investigation of whether blood biomarkers may be important considerations in clinical trials investigating effects of statins on depression.
10.1038/s41398-023-02403-8
Dried fruit intake causally protects against low back pain: A Mendelian randomization study.
Frontiers in nutrition
Background:Low back pain is the leading cause of years lived with disability worldwide. The aim of this study was to evaluate whether dried fruit intake causally protects against low back pain using two-sample Mendelian randomization (MR). Methods:We obtained summary-level data for dried fruit intake ( = 421,764) from the IEU Open GWAS Project. Forty-one independent genetic variants proxied dried fruit intake. The corresponding data for low back pain were derived from the FinnGen project (13,178 cases and 164,682 controls; discovery data) and the Neale lab (5,423 cases and 355,771 controls; replication data). We conducted univariable and multivariable MR analyses. Results:In the univariable MR analysis, the inverse variance weighted estimate showed that greater dried fruit intake was associated with decreased risk of low back pain [odds ratio (OR) = 0.435, 95% confidence interval (CI): 0.287-0.659, = 8.657 × 10]. Sensitivity analyses using the MR-Egger (OR = 0.078, 95% CI: 0.013-0.479, = 0.009), maximum likelihood (OR = 0.433, 95% CI: 0.295-0.635, = 1.801 × 10), weighted median (OR = 0.561, 95% CI: 0.325-0.967, = 0.038) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) (OR = 0.454, 95% CI: 0.302-0.683, = 4.535 × 10) methods showed consistent results. No evidence of directional pleiotropy was identified according to the Egger intercept (intercept -value = 0.065) or applying the MR-PRESSO method (global test -value = 0.164). The replication analysis yielded similar results. The multivariable MR revealed that the inverse association between dried fruit intake and low back pain was consistent after adjustment for fresh fruit intake, body mass index, current tobacco smoking, alcohol intake frequency, total body bone mineral density, serum 25-hydroxyvitamin D levels, and vigorous physical activity. Conclusion:This MR study provides evidence to support that dried fruit intake causally protects against low back pain.
10.3389/fnut.2023.1027481
Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.
Clinical epigenetics
BACKGROUND:Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function. RESULTS:Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR. CONCLUSION:This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.
10.1186/s13148-023-01476-y
Associations of Lipids and Lipid-Lowering Drugs with Risk of Vascular Dementia: A Mendelian Randomization Study.
Nutrients
Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear. Hence, the aim of this study is to infer causal associations of circulating lipid-related traits [including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB)] with VaD jointly using univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR methods. Then, the summary-data-based MR (SMR) and two-sample MR analysis were conducted to investigate the association of lipid-lowering drugs target genes expression (including HMGCR, PCSK9, NPC1L1, and APOB) and LDL-C level mediated by these target genes with VaD. The results of forward MR analyses found that genetically predicted HDL-C, LDL-C, TG, apoA-I, and apoB concentrations were not significantly associated with the risk of VaD (all p > 0.05). Notably, there was suggestive evidence for a causal effect of genetically predicted VaD on HDL-C via reverse MR analysis [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.994−0.999; p = 0.022]. On the contrary, the MR results showed no significant relationship between VaD with LDL-C, TG, apoA-I, and apoB. The results for the SMR method found that there was no evidence of association for expression of HMGCR, PCSK9, NPC1L1, and APOB gene with risk of VaD. Furthermore, the result of MR analysis provided evidence for the decreased LDL-C level mediated by gene HMGCR reduced the risk of VaD (OR, 18.381; 95% CI, 2.092−161.474; p = 0.009). Oppositely, none of the IVW methods indicated any causal effects for the other three genes. Using genetic data, this study provides evidence that the VaD risk may cause a reduction of HDL-C level. Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.
10.3390/nu15010069
The Association between Blood Lipids and Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Research.
Metabolites
We evaluated the causal effects of blood lipid levels on systemic lupus erythematosus with a two-sample Mendelian randomization analysis. Independent single-nucleotide polymorphisms related to blood lipids levels (p < 5 × 10−8) were selected as instrumental variables (IVs) from a published genome-wide association study (GWAS). SLE GWAS analysis that included 4036 cases and 6959 controls of European ancestry provided the related roles between instrumental variables and result (SLE). The causal effects were evaluated with two-sample Mendelian randomization (MR) analyses. According to the inverse-variance weighted approaches, genes predictive of increased LDL cholesterol (OR: 1.131; 95% CI: 0.838, 1.528; p = 0.420), HDL cholesterol (OR: 1.093; 95% CI: 0.884, 1.352; p = 0.412), triglycerides (OR: 0.903; 95% CI: 0.716, 1.137; p = 0.384), Apolipoprotein A-I (OR: 0.854; 95% CI: 0.680, 1.074; p = 0.177), and Apolipoprotein B (OR: 0.933; 95% CI: 0.719, 1.211; p = 0.605) were not causally related to the risk of SLE, consistent with multivariate Mendelian randomization analysis. The reverse-MR analyses showed no massive causal roles between SLE and LDL cholesterol (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.166) as well as Apolipoprotein B (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.229). Nevertheless, a causal role of SLE in decreasing HDL cholesterol (OR: 0.993; 95% CI: 0.988, 0.997; p = 0.002), triglycerides (OR: 0.996; 95% CI: 0.993, 0.999; p = 0.010), and Apolipoprotein A-I (OR: 0.995; 95% CI: 0.990, 0.999; p = 0.026) was validated to some extent. Our study found no causal association between abnormal blood lipids and SLE nor a causal effect between SLE and LDL cholesterol as well as Apolipoprotein B. Nevertheless, some evidence showed that SLE exerted a causal effect on lowering HDL cholesterol, Apolipoprotein A-I, and triglyceride levels.
10.3390/metabo13010027
Linear and Nonlinear Associations Between Vitamin D and Grip Strength: A Mendelian Randomization Study in UK Biobank.
The journals of gerontology. Series A, Biological sciences and medical sciences
BACKGROUND:Low vitamin D status is a widespread phenomenon. Similarly, muscle weakness, often indicated by low grip strength, is another public health concern; however, the vitamin D-grip strength relationship is equivocal. It is important to understand whether variation in vitamin D status causally influences muscle strength to elucidate whether supplementation may help prevent/treat muscle weakness. METHODS:UK Biobank participants, aged 37-73 years, with valid data on Vitamin D status (circulating 25-hydroxyvitamin D [25(OH)D] concentration) and maximum grip strength were included (N = 368,890). We examined sex-specific cross-sectional associations between 25(OH)D and grip strength. Using Mendelian randomization (MR), we estimated the strength of the 25(OH)D-grip strength associations using genetic instruments for 25(OH)D as our exposure. Crucially, because potential effects of vitamin D supplementation on strength could vary by underlying 25(OH)D status, we allowed for nonlinear relationships between 25(OH)D and strength in all analyses. RESULTS:Mean (SD) of 25(OH)D was 50 (21) nmol/L in males and females. In cross-sectional analyses, there was evidence of nonlinear associations between 25(OH)D and strength, for example, compared to males with 50 nmol/L circulating 25(OH)D, males with 75 nmol/L had 0.36 kg (0.31,0.40) stronger grip; males with 25 nmol/L had 1.01 kg (95% confidence interval [CI]: 0.93, 1.08) weaker grip. In MR analyses, linear and nonlinear models fitted the data similarly well, for example, 25 nmol/L higher circulating 25(OH)D in males was associated with 0.25 kg (-0.05, 0.55) greater grip (regardless of initial 25(OH)D status). Results were similar, albeit weaker, for females. CONCLUSIONS:Using two different methods to triangulate evidence, our findings suggest moderate to small causal links between circulating 25(OH)D and grip strength.
10.1093/gerona/glac255
Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.
Journal of Crohn's & colitis
BACKGROUND AND AIMS:Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. METHODS:We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. RESULTS:Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. CONCLUSION:Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.
10.1093/ecco-jcc/jjac191
Causal Associations Between Basal Metabolic Rate and COVID-19.
Diabetes
Many coronavirus disease 2019 (COVID-19) risk factors, including obesity and diabetes, are associated with an abnormal basal metabolic rate (BMR). We aimed to evaluate whether BMR could impact the susceptibility to or severity of COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic correlations and potential causal associations between BMR (n = 448,348) and three COVID-19 outcomes: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, and critical COVID-19 (n = 1,086,211-2,597,856). A multivariable MR (MVMR) analysis was used to estimate the direct effect of BMR on COVID-19 independent of BMI and type 2 diabetes. BMR has positive genetic correlations with the COVID-19 outcomes (genetic correlations 0.213-0.266). The MR analyses indicated that genetic liability to BMR confers causal effects on SARS-CoV-2 infection (odds ratio 1.14, 95% CI 1.09-1.20, P = 1.65E-07), hospitalized COVID-19 (1.31, 1.18-1.46, P = 8.69E-07), and critical COVID-19 (1.04, 1.19-1.64, P = 4.89E-05). Sensitivity analysis of MR showed no evidence of directional pleiotropy or heterogeneity, indicating the robustness of its results. The MVMR analysis showed that the causal effects of BMR on hospitalized COVID-19 and critical COVID-19 were dependent on BMI and type 2 diabetes but that BMR may affect the SARS-CoV-2 infection risk independently of BMI and type 2 diabetes (odds ratio 1.09, 95% CI 1.03-1.15, P = 4.82E-03). Our study indicates that a higher BMR contributes to amplifying the susceptibility to and severity of COVID-19. The causal effect of BMR on the severity of COVID-19 may be mediated by BMI and type 2 diabetes.
10.2337/db22-0610
Shared genetics and causal associations between COVID-19 and multiple sclerosis.
Journal of medical virology
Neuroinflammation caused by COVID-19 negatively impacts brain metabolism and function, while pre-existing brain pathology may contribute to individuals' vulnerability to the adverse consequences of COVID-19. We used summary statistics from genome-wide association studies (GWAS) to perform Mendelian randomization (MR) analyses, thus assessing potential associations between multiple sclerosis (MS) and two COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and COVID-19 hospitalization). Genome-wide risk genes were compared between the GWAS datasets on hospitalized COVID-19 and MS. Literature-based analysis was conducted to construct molecular pathways connecting MS and COVID-19. We found that genetic liability to MS confers a causal effect on hospitalized COVID-19 (odd ratio [OR]: 1.09, 95% confidence interval: 1.03-1.16) but not on SARS-CoV-2 infection (1.03, 1.00-1.05). Genetic liability to hospitalized COVID-19 confers a causal effect on MS (1.15, 1.02-1.30). Hospitalized COVID-19 and MS share five risk genes within two loci, including TNFAIP8, HSD17B4, CDC37, PDE4A, and KEAP1. Pathway analysis identified a panel of immunity-related genes that may mediate the links between MS and COVID-19. Our study suggests that MS was associated with a 9% increased risk for COVID-19 hospitalization, while hospitalized COVID-19 was associated with a 15% increased risk for MS. Immunity-related pathways may underlie the link between MS on COVID-19.
10.1002/jmv.28431
Fibroblast Growth Factor-23 and Risk of Cardiovascular Diseases: A Mendelian Randomization Study.
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND:Fibroblast growth factor-23 (FGF-23) is associated with a range of cardiovascular and noncardiovascular diseases in conventional epidemiological studies, but substantial residual confounding may exist. Mendelian randomization approaches can help control for such confounding. METHODS:SCALLOP Consortium data of 19,195 participants were used to generate an FGF-23 genetic score. Data from 337,448 UK Biobank participants were used to estimate associations between higher genetically predicted FGF-23 concentration and the odds of any atherosclerotic cardiovascular disease (n=26,266 events), nonatherosclerotic cardiovascular disease (n=12,652), and noncardiovascular diseases previously linked to FGF-23. Measurements of carotid intima-media thickness and left ventricular mass were available in a subset. Associations with cardiovascular outcomes were also tested in three large case-control consortia: CARDIOGRAMplusC4D (coronary artery disease, n=181,249 cases), MEGASTROKE (stroke, n=34,217), and HERMES (heart failure, n=47,309). RESULTS:We identified 34 independent variants for circulating FGF-23, which formed a validated genetic score. There were no associations between genetically predicted FGF-23 and any of the cardiovascular or noncardiovascular outcomes. In UK Biobank, the odds ratio (OR) for any atherosclerotic cardiovascular disease per 1-SD higher genetically predicted logFGF-23 was 1.03 (95% confidence interval [95% CI], 0.98 to 1.08), and for any nonatherosclerotic cardiovascular disease, it was 1.01 (95% CI, 0.94 to 1.09). The ORs in the case-control consortia were 1.00 (95% CI, 0.97 to 1.03) for coronary artery disease, 1.01 (95% CI, 0.95 to 1.07) for stroke, and 1.00 (95% CI, 0.95 to 1.05) for heart failure. In those with imaging, logFGF-23 was not associated with carotid or cardiac abnormalities. CONCLUSIONS:Genetically predicted FGF-23 levels are not associated with atherosclerotic and nonatherosclerotic cardiovascular diseases, suggesting no important causal link. PODCAST:This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_01_10_CJN05080422.mp3.
10.2215/CJN.05080422
Causal relationship between moderate to vigorous physical activity and venous thromboembolism.
Journal of thrombosis and thrombolysis
Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66-1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01-4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52-2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59-10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50-9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46-1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population.
10.1007/s11239-022-02754-x
Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study.
Arteriosclerosis, thrombosis, and vascular biology
BACKGROUND:Observational studies identified elevated blood pressure (BP) as a strong risk factor for thoracic aortic dilation, and BP reduction is the primary medical intervention recommended to prevent progression of aortic aneurysms. However, although BP may impact aortic dilation, aortic size may also impact BP. The causal relationship between BP and thoracic aortic size has not been reliably established. METHODS:Genome-wide association studies summary statistics were obtained for BP and ascending thoracic aortic diameter (AscAoD). Causal effects of BP on AscAoD were estimated using 2-sample Mendelian randomization using a range of pleiotropy-robust methods. RESULTS:Genetically predicted increased systolic BP, diastolic BP, and mean arterial pressure all significantly associate with higher AscAoD (systolic BP: β estimate, 0.0041 mm/mm Hg [95% CI, 0.0008-0.0074]; =0.02, diastolic BP: β estimate, 0.0272 mm/mm Hg [95% CI, 0.0224-0.0320]; <0.001, and mean arterial pressure: β estimate, 0.0168 mm/mm Hg [95% CI, 0.0130-0.0206]; <0.001). Genetically predicted pulse pressure, meanwhile, had an inverse association with AscAoD (β estimate, -0.0155 mm/mm Hg [95% CI, -0.0213 to -0.0096]; <0.001). Multivariable Mendelian randomization analyses showed that genetically predicted increased mean arterial pressure and reduced pulse pressure were independently associated with AscAoD. Bidirectional Mendelian randomization demonstrated that genetically predicted AscAoD was inversely associated with pulse pressure (β estimate, -2.0721 mm Hg/mm [95% CI, -3.1137 to -1.0306]; <0.001) and systolic BP (β estimate, -1.2878 mm Hg/mm [95% CI, -2.3533 to -0.2224]; =0.02), while directly associated with diastolic BP (0.8203 mm Hg/mm [95% CI, 0.2735-1.3672]; =0.004). CONCLUSIONS:BP likely contributes causally to ascending thoracic aortic dilation. Increased AscAoD likely contributes to lower systolic BP and pulse pressure, but not diastolic BP, consistent with the hemodynamic consequences of a reduced aortic diameter.
10.1161/ATVBAHA.122.318149
Impact of genetically predicted atrial fibrillation on cancer risks: A large cardio-oncology Mendelian randomization study using UK biobank.
Frontiers in cardiovascular medicine
Background:Increasing incidences of both atrial fibrillation (AF) and cancer have been observed in recent years. However, the casual association of both serious conditions has been scarcely evaluated and is considered to be a blank slate in cardio-oncology. Thus, we introduced Mendelian randomization (MR) methods to estimate the effects of AF on cancer risks. Methods:We performed univariable and multivariable two-sample MR analyses to evaluate the effects of AF on the risk of 19 site-specific types of cancer. This MR study was conducted based on 111 independent AF-associated genetic instruments from genome-wide association studies and summarized-level data from corresponding cancer consortia. Multiple sensitivity analyses, including the leave-one-out analysis, MR-Egger regression, and MR-PRESSO tests, were further performed to examine the potential directional pleiotropic effects. Functional annotation was performed for common differentially expressed genes of AF and prostate cancer (PCA). Results:A total of 6,777,155 European-descent people, including 533,725 cases and 6,243,430 controls, were included in the present MR analysis. Univariable MR analyses demonstrated a causal effect of AF on the incidence of PCA [odds ratio (OR): 0.96; 95% confidence interval (CI) 0.92-0.99, = 0.01], and the causal effect remained significant (OR: 0.65; 95% CI 0.47-0.90, = 0.01) after adjusting for potential confounders through the multivariable MR approach. However, no casual associations between AF and the other 18 site-specific cancer risks were observed (all -values were > 0.05). The consistency of outcomes across complementary sensitivity MR methods further supported the causality. The functional analysis emphasized the essential role of antioxidant and xenobiotic catabolic processes in AF and PCA. Conclusion:Contrary to the findings of several previous observational studies, our comprehensive MR analyses did not corroborate a causal role for AF in increasing the risk of various types of cancer. They did, however, demonstrate that AF may decrease the risk of PCA. Studies from larger sample sizes and individuals with different ethnic backgrounds are required to further support our conclusions.
10.3389/fcvm.2022.974402
Systolic blood pressure as the mediator of the effect of early menarche on the risk of coronary artery disease: A Mendelian randomization study.
Frontiers in cardiovascular medicine
Background:Menarche timing may not be directly associated with the risk of coronary artery disease (CAD). Therefore, we investigated the roles of metabolic factors in explaining the effect of age at menarche on CAD risk. Methods:We identified women with age at menarche and CAD by using three analytical methods: Mendelian randomization (MR), logistic regression analysis, and Cox proportional hazard regression. The first two analyses were performed in the Taiwan Biobank ( = 71,923) study, and the last analysis was performed in the Chin-Shan Community Cardiovascular Cohort study ( = 1,598). We further investigated the role of metabolic factors in mediating the effect of age at menarche on CAD risk by using three complementary methods with mediation analyses. Results:One standard deviation of earlier age at menarche was associated with a 2% higher CAD risk [odds ratio = 1.02, 95% confidence interval (CI) = 1.001-1.03] in the MR analysis, an 11% higher risk (odds ratio = 1.11, 95% CI = 1.02-1.21) in the logistic regression analysis, and a 57% higher risk (hazard ratio = 1.57, 95% CI = 1.12-2.19) in the Cox proportional hazard regression. All the analyses consistently supported the role of systolic blood pressure in mediating this effect. The MR results indicated that 29% (95% CI = 26%-32%) of the effect of genetically predicted earlier age at menarche on CAD risk was mediated by genetically predicted systolic blood pressure. Conclusion:The results obtained using different analytical methods suggest that interventions aimed at lowering systolic blood pressure can reduce the cases of CAD attributable to earlier age at menarche.
10.3389/fcvm.2022.1023355
Dissecting Causal Associations of Diet-Derived Circulating Antioxidants with Six Major Mental Disorders: A Mendelian Randomization Study.
Antioxidants (Basel, Switzerland)
Although observational studies have suggested associations between circulating antioxidants and many mental disorders, causal inferences have not been confirmed. Mendelian randomization (MR) analyses were conducted using summary-level statistics from genome-wide association studies (GWASs) to explore whether genetically determined absolute circulating antioxidants (i.e., ascorbate, retinol, β-carotene, and lycopene) and metabolites (i.e., α- and γ-tocopherol, ascorbate, and retinol) were causally associated with the risk of six major mental disorders, including anxiety disorders (AD), major depressive disorder (MDD), bipolar disorder (BIP), schizophrenia (SCZ), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). MR analyses were performed per specific-outcome databases, including the largest GWAS published to date (from 9725 for OCD to 413,466 for BIP participants), UK Biobank (over 370,000 participants), and FinnGen (over 270,000 participants), followed by meta-analyses. We found no significant evidence that genetically determined diet-derived circulating antioxidants were significantly causally associated with the risk of the six above-mentioned major mental disorders. For absolute antioxidant levels, the odds ratios (ORs) ranged from 0.91 (95% CI, 0.67-1.23) for the effect of β-carotene on OCD to 1.18 (95% CI, 0.90-1.54) for the effect of ascorbate on OCD. Similarly, for antioxidant metabolites, ORs ranged from 0.87 (95% CI, 0.55-1.38) for the effect of ascorbate on MDD to 1.08 (95% CI, 0.88-1.33) for the effect of ascorbate on OCD. Our study does not support significant causal associations of genetically determined diet-derived circulating antioxidants with the risk of major mental disorders.
10.3390/antiox12010162
Causal relationships of excessive daytime napping with atherosclerosis and cardiovascular diseases: a Mendelian randomization study.
Sleep
STUDY OBJECTIVES:Previous observational studies have found conflicting evidence on the relationship between daytime napping and incident cardiovascular diseases (CVDs), but it remains unclear whether these associations present causality. This study aims to verify whether and why there is a causal relationship between these parameters, and whether there is an etiological basis. METHODS:A two-sample Mendelian randomization analysis was performed using 79 single nucleotide polymorphisms associated with daytime napping. Summary-level data for coronary atherosclerosis, peripheral atherosclerosis, total CVD, and five CVD outcomes were obtained from the FinnGen study. Meta-analyses were aimed at investigating the relationships of excessive daytime napping with total CVD, coronary heart disease, myocardial infarction (MI), and stroke incidence. Subgroup, network meta-analysis (NMA) and trial sequential analysis (TSA) were also performed in this study. RESULTS:The inverse-variance weighted method demonstrated that a genetic predisposition to more frequent daytime napping was significantly associated with higher odds of coronary atherosclerosis (odds ratio [OR] = 1.55, 95% confidence interval [CI]: 1.11 to 2.17), MI (OR = 1.63, 95% CI: 1.06 to 2.50), and heart failure (OR = 1.80, 95%CI: 1.28 to 2.52). In NMA, an increased risk of developing CVD in people who napped for more than 60 min a day than those who did not nap was demonstrated and then supported by TSA results (summary relative risk = 1.98, 95% CI: 1.39 to 2.82). CONCLUSION:Habitual daytime napping is causally associated with an increased risk of incident CVD primarily via the development of coronary atherosclerosis. An average napping duration of more than 60 min is associated with an elevated risk of CVD in all participants.
10.1093/sleep/zsac257
The gut microbiome and hypertension.
Nature reviews. Nephrology
A large body of evidence has emerged in the past decade supporting a role for the gut microbiome in the regulation of blood pressure. The field has moved from association to causation in the last 5 years, with studies that have used germ-free animals, antibiotic treatments and direct supplementation with microbial metabolites. The gut microbiome can regulate blood pressure through several mechanisms, including through gut dysbiosis-induced changes in microbiome-associated gene pathways in the host. Microbiota-derived metabolites are either beneficial (for example, short-chain fatty acids and indole-3-lactic acid) or detrimental (for example, trimethylamine N-oxide), and can activate several downstream signalling pathways via G protein-coupled receptors or through direct immune cell activation. Moreover, dysbiosis-associated breakdown of the gut epithelial barrier can elicit systemic inflammation and disrupt intestinal mechanotransduction. These alterations activate mechanisms that are traditionally associated with blood pressure regulation, such as the renin-angiotensin-aldosterone system, the autonomic nervous system, and the immune system. Several methodological and technological challenges remain in gut microbiome research, and the solutions involve minimizing confounding factors, establishing causality and acting globally to improve sample diversity. New clinical trials, precision microbiome medicine and computational methods such as Mendelian randomization have the potential to enable leveraging of the microbiome for translational applications to lower blood pressure.
10.1038/s41581-022-00654-0
Serum 25-Hydroxyvitamin D and Cancer Risk: A Systematic Review of Mendelian Randomization Studies.
Nutrients
Epidemiological studies suggest that higher serum 25-hydroxyvitamin D is associated with lower risk for several cancers, including breast, prostate, colorectal, and lung cancers. To mitigate confounding, genetic instrumental variables (IVs) have been used to estimate causal associations between 25-hydroxivtamin D and cancer risk via Mendelian randomization (MR). We provide a systematic review of 31 MR studies concerning 25-hydroxyvitamin D and cancer incidence and mortality identified from biomedical databases. MR analyses were conducted almost exclusively in European-ancestry populations and identified no statistically significant associations between higher genetically predicted 25-hydroxyvitamin D and lower risk for total cancer or colorectal, breast, prostate, lung, or pancreatic cancers. In recent studies including ≥80 genetic IVs for 25-hydroxyvitamin D, null associations were reported for total cancer (odds ratio [95% confidence interval] per 1-standard deviation increase: 0.98 [0.93-1.04]), breast (1.00 [0.98-1.02]), colorectal (0.97 [0.88-1.07]), prostate (0.99 [0.98-1.01]), and lung cancer (1.00 [0.93-1.03]). A protective association was observed for ovarian cancer in the Ovarian Cancer Association Consortium (0.78 [0.63-0.96] per 20 nmol/L increase, -trend = 0.03), but not in the UK Biobank (1.10 [0.80-1.51]). Null associations were reported for other tumor sites (bladder, endometrium, uterus, esophagus, oral cavity and pharynx, kidney, liver, thyroid, or neural cells). An inconsistent protective association for cancer-specific mortality was also observed. Results from MR analyses do not support causal associations between 25-hydroxyvitamin D and risk for cancer incidence or mortality. Studies including non-White populations may be valuable to understand low 25-hydroxyvitamin D as a modifiable risk factor in populations with a higher risk of common cancers, including African ancestry individuals.
10.3390/nu15020422
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
Antioxidants, minerals and vitamins in relation to Crohn's disease and ulcerative colitis: A Mendelian randomization study.
Alimentary pharmacology & therapeutics
BACKGROUND:Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC. METHODS:Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed. RESULTS:Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91-0.97), vitamins D (OR = 0.65, 95% CI: 0.54-0.79) and K1 (OR = 0.93, 95% CI: 0.90-0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23-1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88-0.95), phosphorus (OR = 0.69, 95% CI: 0.58-0.82), selenium (OR = 0.91, 95% CI: 0.85-0.97), zinc (OR = 0.91, 95% CI: 0.89-0.94), folate (OR = 0.71, 95% CI: 0.56-0.92) and vitamin E (OR = 0.78, 95% CI: 0.69-0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22-1.76) and magnesium (OR = 1.24, 95% CI: 1.03-1.49) were associated with increased risk of UC. CONCLUSIONS:Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.
10.1111/apt.17392
Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration.
eLife
Background:Age-related macular degeneration (AMD) is a leading cause of blindness in the industrialised world and is projected to affect >280 million people worldwide by 2040. Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study. Methods:We evaluated the effect of 4591 exposure traits on early AMD using univariable MR. Statistically significant results were explored further using: validation in an advanced AMD cohort; MR Bayesian model averaging (MR-BMA); and multivariable MR. Results:Overall, 44 traits were found to be putatively causal for early AMD in univariable analysis. Serum proteins that were found to have significant relationships with AMD included S100-A5 (odds ratio [OR] = 1.07, p-value = 6.80E-06), cathepsin F (OR = 1.10, p-value = 7.16E-05), and serine palmitoyltransferase 2 (OR = 0.86, p-value = 1.00E-03). Univariable MR analysis also supported roles for complement and immune cell traits. Although numerous lipid traits were found to be significantly related to AMD, MR-BMA suggested a driving causal role for serum sphingomyelin (marginal inclusion probability [MIP] = 0.76; model-averaged causal estimate [MACE] = 0.29). Conclusions:The results of this MR study support several putative causal factors for AMD and highlight avenues for future translational research. Funding:This project was funded by the Wellcome Trust (224643/Z/21/Z; 200990/Z/16/Z); the University of Manchester's Wellcome Institutional Strategic Support Fund (Wellcome ISSF) grant (204796/Z/16/Z); the UK National Institute for Health Research (NIHR) Academic Clinical Fellow and Clinical Lecturer Programmes; Retina UK and Fight for Sight (GR586); the Australian National Health and Medical Research Council (NHMRC) (1150144).
10.7554/eLife.82546
Causal association of leisure sedentary behavior with arthritis: A Mendelian randomization analysis.
Seminars in arthritis and rheumatism
OBJECTIVES:This study aimed at exploring the potential causal effects of leisure sedentary behavior (LSB) on common types of arthritis. METHOD:Two-sample Mendelian randomization (MR), including both univariable MR (UVMR) and multivariable MR (MVMR) analysis, was performed to explore the effects of LSB on the risk of several common types of arthritis, including osteoarthritis, rheumatoid arthritis (RA), and psoriatic arthritis (PsA). Genetic variants from genome-wide association studies (GWAS) of LSBs for time spent on television watching, computer use, and driving were obtained from the UK Biobank. Summarized GWAS data of OA [overall, OA of the hip (HOA), and OA of the knee (KOA)], RA [overall, seronegative RA (nRA) and seropositive RA], and PsA was also acquired from the FinnGen Biobank Analysis. Causal Analysis Using Summary Effect Estimates (CAUSE) were further applied to verify the causality. RESULTS:UVMR results provided evidence for the causal relationship of time spent on watching TV with overall OA [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.45-2.23], KOA (OR = 1.86, 95% CI = 1.45-2.39) and HOA (IVW-fixed: OR = 1.65, 95% CI =1.20-2.26). Similar associations were observed in the TV-overall RA and TV-pRA, and TV-PsA, but the CAUSE method results only supported the causal association of time spent TV watching with OA and KOA. Moreover, MVMR results showed indicated an independent causal effect of TV watching on OA (overall, KOA, and HOA). CONCLUSION:This study demonstrated the genetic causal association of prolonged TV watching time with overall OA and KOA risks.
10.1016/j.semarthrit.2023.152171
Shared genetics of psychiatric disorders and type 2 diabetes:a large-scale genome-wide cross-trait analysis.
Journal of psychiatric research
BACKGROUND:Individuals with psychiatric disorders have elevated rates of type 2 diabetes comorbidity. Although little is known about the shared genetics and causality of this association. Thus, we aimed to investigate shared genetics and causal link between different type 2 diabetes and psychiatric disorders. METHODS:We conducted a large-scale genome-wide cross-trait association study(GWAS) to investigate genetic overlap between type 2 diabetes and anorexia nervosa, attention deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, anxiety disorders and Tourette syndrome. By post-GWAS functional analysis, we identify variants genes expression in various tissues. Enrichment pathways, potential protein interaction and mendelian randomization also provided to research the relationship between type 2 diabetes and psychiatric disorders. RESULTS:We discovered that type 2 diabetes and psychiatric disorders had a significant correlation. We identified 138 related loci, 32 were novel loci. Post-GWAS analysis revealed that 86 differentially expressed genes were located in different brain regions and peripheral blood in type 2 diabetes and related psychiatric disorders. MAPK signaling pathway plays an important role in neural development and insulin signaling. In addition, there is a causal relationship between T2D and mental disorders. In PPI analysis, the central genes of the DEG PPI network were FTO and TCF7L2. CONCLUSION:This large-scale genome-wide cross-trait analysis identified shared genetics andpotential causal links between type 2 diabetes and related psychiatric disorders, suggesting potential new biological functions in common among them.
10.1016/j.jpsychires.2023.01.037
Association between genetically predicted leukocyte telomere length and non-scarring alopecia: A two-sample Mendelian randomization study.
Frontiers in immunology
Background:The most commonly acknowledged non-scarring alopecia are androgenetic alopecia (AGA) and alopecia areata (AA). Previous studies have revealed various risk factors associated with alopecia. However, the relationship between leukocyte telomere length (LTL) and non-scarring alopecia remains unclear. Methods:A two-sample Mendelian randomization (MR) analysis was performed to evaluate the causality between genetically predicted LTL and the risk of non-scarring alopecia. MR analyses were performed using the inverse variance-weighted (IVW) method and complemented with other MR methods. Results:The summary statistics of the genome-wide association studies (GWAS) for AGA and AA were obtained from the FinnGen biobank, which included 119,185 and 211,428 individuals, respectively. A total of 126 single nucleotide polymorphisms (SNPs) with genome-wide significance were selected as the instrumental variables for LTL. The MR analyses suggested a causal relationship between LTL and AGA, and the risk of AGA increased by 3.19 times as the genetically predicted LTL was shortened by one standard deviation in log transformed form under the IVW method (OR = 4.19, 95% CI = 1.20-14.61, = 0.024). The other MR methods also demonstrated a similar trend of the effect of LTL on AGA. There was no causal relationship between LTL and AA ( > 0.05). Sensitivity analyses further demonstrated that the current results were less likely to be affected by confounders and bias. Conclusion:Our results suggested a potential causal relationship between LTL and AGA, and shortened LTL was associated with an increased risk of AGA.
10.3389/fimmu.2022.1072573
Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.
PLoS medicine
BACKGROUND:Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. METHODS AND FINDINGS:We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. CONCLUSIONS:IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.
10.1371/journal.pmed.1004174
Sepsis as an independent risk factor in atrial fibrillation and cardioembolic stroke.
Frontiers in endocrinology
Background:Electrolyte balance is an important factor to sustain the homeostasis of human body environment and in sepsis pathogenesis. Many current cohort-based studies have already revealed that electrolyte disorder may intensify sepsis and induce stroke. However, the corresponding randomized controlled trials did not show that electrolyte disorder in sepsis has a harmful effect on stroke. Objectives:The aim of this study was to examine the association of genetically sepsis-derived electrolyte disorder with stroke risk using meta-analysis and Mendelian randomization. Results:In four studies (182,980 patients), electrolyte disorders were compared with stroke incidence in patients with sepsis. The pooled odds ratio (OR) of stroke is 1.79 [95% confidence interval (CI): 1.23-3.06; < 0.05], which shows a significant association between electrolyte disorder and stroke in sepsis patients. Furthermore, in order to evaluate the causal association between stroke risk and sepsis-derived electrolyte disorder, a two-sample Mendelian randomization (MR) study was conducted. The genetic variants extracted from a genome-wide association study (GWAS) of exposure data that are strongly associated with frequently used sepsis were used as instrumental variables (IVs). Based on the IVs' corresponding effect estimates, we estimated overall stroke risk, cardioembolic stroke risk, and stroke induced by large/small vessels from a GWAS meta-analysis with 10,307 cases and 19,326 controls. As a final step to verify the preliminary MR results, we performed sensitivity analysis using multiple types of Mendelian randomization analysis. Conclusion:Our study revealed the association between electrolyte disorder and stroke in sepsis patients, and the correlation between genetic susceptibility to sepsis and increased risk of cardioembolic stroke, hinting that cardiogenic diseases and accompanying electrolyte disorder interference in due course could help sepsis patients get more benefits in stroke prevention.
10.3389/fendo.2023.1056274
Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study.
Obesity (Silver Spring, Md.)
OBJECTIVE:Although the association between adiposity and gastrointestinal (GI) diseases has been explored, the causal effects of adiposity on GI diseases are largely unknown. METHODS:Mendelian randomization was conducted using single-nucleotide polymorphisms associated with BMI and waist circumference (WC) as instrumental variables, and the causal associations of BMI or WC with GI conditions were estimated among >400,000 UK Biobank participants, >170,000 Finnish-descent participants, and numerous consortia participants of predominantly European ancestry. RESULTS:Genetically predicted BMI was robustly associated with increased risk of nonalcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. For the diseases, the odds ratio per 1-SD increase in genetically predicted BMI (4.77 kg/m ) ranged from 1.22 (95% CI: 1.12-1.34; p < 0.0001) for NAFLD to 1.65 (95% CI: 1.31-2.06; p < 0.0001) for cholecystitis. Genetically predicted WC was robustly associated with increased risk of NAFLD, alcoholic liver disease, cholecystitis, cholelithiasis, colon cancer, and gastric cancer. Alcoholic liver disease was consistently associated with WC even after adjusting for alcohol consumption in a multivariable Mendelian randomization analysis. The odds ratio per 1-SD increase in genetically predicted WC (12.52 cm) for such associations ranged from 1.41 (95% CI: 1.17-1.70; p = 0.0015) for gastric cancer to 1.74 (95% CI: 1.21-1.78; p < 0.0001) for cholelithiasis. CONCLUSIONS:High genetically predicted adiposity was causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism.
10.1002/oby.23722
Causal effects of inflammatory protein biomarkers on inflammatory diseases.
Science advances
Many circulating proteins are associated with the presence or severity of disease. However, whether these protein biomarkers are causal for disease development is usually unknown. We investigated the causal effect of 21 well-known or exploratory protein biomarkers of inflammation on 18 inflammatory diseases using two-sample Mendelian randomization. We identified six proteins to have causal effects on any of 11 inflammatory diseases (FDR < 0.05, corresponding to < 1.4 × 10). IL-12B protects against psoriasis and psoriatic arthropathy, LAP-TGF-β-1 protects against osteoarthritis, TWEAK protects against asthma, VEGF-A protects against ulcerative colitis, and LT-α protects against both type 1 diabetes and rheumatoid arthritis. In contrast, IL-18R1 increases the risk of developing allergy, hay fever, and eczema. Most proteins showed protective effects against development of disease rather than increasing disease risk, which indicates that many disease-related biomarkers are expressed to protect from tissue damage. These proteins represent potential intervention points for disease prevention and treatment.
10.1126/sciadv.abl4359
An inverse causal association between genetically predicted vitamin D and chronic obstructive pulmonary disease risk.
Frontiers in nutrition
Aim:Observational studies have reported that levels of vitamin D were associated with the incidence of chronic obstructive pulmonary disease (COPD), but the relationship between them may have been confounded in previous studies. In this study, we aimed to determine the relationship between the levels of 25-hydroxyvitamin D (25OHD) and the risk of COPD by two-sample Mendelian randomization (MR) analysis. Methods:Summary statistics for 25OHD and COPD in this study were obtained from the EBI ( = 496,946) consortium and Finn ( = 187,754) consortium. MR was adopted to explore the effect of the genetically predicted levels of 25OHD on the risk of COPD. Based on three assumptions of MR analysis, inverse variance weighting was used as the main analysis. To make our results more robust and reliable, MR Egger's intercept test, Cochran's Q test, funnel plot, and "leave-one-out" sensitivity analysis were used to assess the potential pleiotropy and heterogeneity in this study. Then, colocalization analysis and MR Steiger approaches were used to estimate the possible directions of estimates between them. Finally, we analyzed the causal associations between the four core genes (DHCR7, GC, CYP2R1, and CYP24A1) of vitamin D and the levels of 25OHD or the risk of COPD. Results:Our results showed that each 1 standard deviation (SD) increase in the genetically predicted 25OHD level was associated with a 57.2% lower relative risk of COPD [odds ratio (OR): 0.428, 95% Cl: 0.279-0.657, = 1.041 × 10], and the above association was also verified by maximum likelihood (OR: 0.427, 95% Cl: 0.277-0.657, = 1.084 × 10), MR-Egger (OR: 0.271, 95% CI: 0.176-0.416, = 2.466 × 10), MR-PRESSO (OR: 0.428, 95% Cl: 0.281-0.652, = 1.421 × 10) and MR-RAPS (OR: 0.457, 95% Cl: 0.293-0.712, = 5.450 × 10). Furthermore, colocalization analyses (rs3829251, PP.H4 = 0.99) and MR Steiger ("TRUE") also showed a reverse association between them. Besides, the core genes of vitamin D also showed similar results except for CYP24A1. Conclusion:Our findings provide evidence for a reverse association between genetically predicted 25OHD levels and COPD risk. Taking measures to supplement 25OHD may help reduce the incidence of COPD.
10.3389/fnut.2023.1111950
Conventional and genetic associations between resting heart rate, cardiac morphology and function as assessed by magnetic resonance imaging: Insights from the UK biobank population study.
Frontiers in cardiovascular medicine
Aim:To examine the direction, strength and causality of the associations of resting heart rate (RHR) with cardiac morphology and function in 20,062 UK Biobank participants. Methods and results:Participants underwent cardiac magnetic resonance (CMR) and we extracted CMR biventricular structural and functional metrics using automated pipelines. Multivariate linear regression adjusted for the main cardiovascular risk factors and Two-sample Mendelian Randomization analyses were performed to assess the potential relationship, grouped by heart rate and stratified by sex. Each 10 beats per minute increase in RHR was linked with smaller ventricular structure (lower biventricular end-diastolic volume and end-systolic volume), poorer left ventricular (LV) function (lower LV ejection fraction, global longitude strain and global function index) and unhealthy pattern of LV remodeling (higher values of myocardial contraction fraction), but there is no statistical difference in LV wall thickness. These trends are more pronounced among males and consistent with the causal effect direction of genetic variants interpretation. These observations reflect that RHR has an independent and broad impact on LV remodeling, however, genetically-predicted RHR is not statistically related to heart failure. Conclusion:We demonstrate higher RHR cause smaller ventricular chamber volume, poorer systolic function and unhealthy cardiac remodeling pattern. Our findings provide effective evidence for the potential mechanism of cardiac remodeling and help to explore the potential scope or benefit of intervention.
10.3389/fcvm.2023.1110231
Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.
Biological psychiatry
BACKGROUND:Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been unclear. METHODS:We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in the UK Biobank (n = 29,757). We then applied two-sample bidirectional Mendelian randomization and colocalization analysis to identify potentially causal relationships between each metabolite and MDD. RESULTS:A total of 191 metabolites tested were significantly associated with MDD (false discovery rate-corrected p < .05), which decreased to 129 after adjustment for likely confounders. Lower abundance of omega-3 fatty acid measures and a higher omega-6 to omega-3 ratio showed potentially causal effects on liability to MDD. There was no evidence of a causal effect of MDD on metabolite levels. Furthermore, genetic signals associated with docosahexaenoic acid colocalized with loci associated with MDD within the fatty acid desaturase gene cluster. Post hoc Mendelian randomization of gene-transcript abundance within the fatty acid desaturase cluster demonstrated a potentially causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but rather the likely existence of two variants in linkage disequilibrium with one another. CONCLUSIONS:Our findings suggest that decreased docosahexaenoic acid and increased omega-6 to omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support for the causal involvement of fatty acids in MDD.
10.1016/j.biopsych.2023.01.027
Disentangling the relationship between depression and chronic widespread pain: A Mendelian randomisation study.
Seminars in arthritis and rheumatism
OBJECTIVE:Depression and chronic widespread pain (CWP) frequently coexist, but whether depression is an independent causal risk factor for CWP, and/or vice versa, remains unclear. We investigated the bidirectional causal relationship between depression and CWP. METHODS:We performed a two-sample Mendelian randomisation (MR) study to estimate the causal relationship between genetically predicted depression (170,756 cases, 329,443 controls) and risk of CWP (6,914 cases, 242,929 controls), and the effect of CWP on depression susceptibility, using large population-level genetic data. We used a new MR method, Causal Analysis Using Summary Effect estimates (CAUSE), which allows for sample overlap, in addition to traditional MR and sensitivity analyses. RESULTS:For each doubling in odds of genetic liability to depression, the risk of chronic widespread pain was increased (OR 1.004, 95% credible interval 1.003-1.005; p = 7.3 × 10 that the causal model is a better fit than non-causal model). There was bidirectional evidence of causality, with genetic liability to chronic widespread pain increasing depression susceptibility (OR 2.31; 95%CrI 1.57, 3.40; p = 0.0026 that the causal model is a better fit). Other MR methods produced concordant results. CONCLUSIONS:This study provides evidence in support of a bidirectional causal relationship between depression and increased risk of chronic widespread pain, whilst overcoming the major limitations of previous epidemiological studies. Interventions for depression may be an effective strategy to prevent or reduce the burden of chronic widespread pain and vice versa.
10.1016/j.semarthrit.2023.152188
Association between antihypertensive drugs and hepatocellular carcinoma: A trans-ancestry and drug-target Mendelian randomization study.
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND AND AIMS:Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear. METHODS:A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis. RESULTS:Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]: 0.79 [0.73, 0.86] per 1 mmHg reduction in SBP; p < 0.001) and East Asians (0.60 [0.45, 0.82]; p = 0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12, 1.91]; p = 0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs. CONCLUSIONS:Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.
10.1111/liv.15566
Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study.
Frontiers in cardiovascular medicine
Background:In recent years, the incidence rates of rheumatoid arthritis (RA) and heart disease (HD) have noticeably increased worldwide. Previous studies have found that patients with RA are more likely to develop HD, while the cause and effect have still remained elusive. In this study, Mendelian randomization (MR) analysis was used to indicate whether there was a potential association between RA and HD. Methods:Data of RA, ischemic heart disease (IHD), myocardial infarction (MI), atrial fibrillation (AF), and arrhythmia were based on the genome-wide association study (GWAS) dataset. No disease group was intersected. Inverse-variance weighted (IVW) method was used to calculate MR estimates, and sensitivity analysis was performed. Results:The primary MR analysis showed that genetic susceptibility to RA was significantly associated with the risk of IHD and MI, rather than with AF and arrhythmia. Besides, there was no heterogeneity and horizontal pleiotropy between the primary and replicated analyses. There was a significant correlation between RA and the risk of IHD (odds ratio (OR), 1.0006; 95% confidence interval (CI), 1.000244-1.00104; = 0.001552), meanwhile, there was a significant correlation between RA and the risk of MI (OR, 1.0458; 95% CI, 1.07061-1.05379; = 0.001636). The results were similar to those of sensitivity analysis, and the sensitivity analysis also verified the conclusion. Furthermore, sensitivity and reverse MR analyses suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between RA and cardiovascular comorbidity. Conclusion:RA was noted to be causally associated with IHD and MI, rather than with AF and arrhythmia. This MR study might provide a new genetic basis for the causal relationship between RA and the risk of CVD. The findings suggested that the control of RA activity might reduce the risk of cardiovascular disease.
10.3389/fcvm.2023.1099861
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
Causal relationship between polycystic ovary syndrome and chronic kidney disease: A Mendelian randomization study.
Frontiers in endocrinology
Objective:Polycystic ovary syndrome is one of the most common endocrine disorders among women of childbearing age. The relationship between polycystic ovary syndrome and chronic kidney disease remains unclear and controversial. In this study, we investigated the causal role of polycystic ovary syndrome in the development of chronic kidney disease using the two-sample Mendelian randomization method. Methods:Public shared summary-level data was acquired from European-ancestry genome wide association studies. We finally obtained 12 single nucleotide polymorphisms as instrumental variables, which were associated with polycystic ovary syndrome in European at genome-wide significance (P < 5 × 10). Inverse-variance weighted method was employed in the Mendelian randomization analysis and multiple sensitivity analyses were implemented. Outcome data were obtained from the Open GWAS database. Results:A positive causal association was observed between polycystic ovary syndrome and chronic kidney disease (odds ratio [OR]=1.180, 95% confidence interval [CI]: 1.038-1.342; P=0.010). Further analyses clarified that causal relationship exist between polycystic ovary syndrome and some serological indicators of chronic kidney disease (fibroblast growth factor 23: OR= 1.205, 95% CI: 1.031-1.409, P=0.019; creatinine: OR= 1.012, 95% CI: 1.001-1.023, P=0.035; cystatin C: OR= 1.024, 95% CI: 1.006-1.042, P=0.009). However, there was no causal association of polycystic ovary syndrome with other factors in the data sources we employed. Conclusions:Our results indicate an important role of polycystic ovary syndrome in the development of chronic kidney disease. This study suggests that regular follow-up of renal function in patients with polycystic ovary syndrome is necessary for the early treatment of chronic kidney disease.
10.3389/fendo.2023.1120119
Cortisol and periodontitis: Prospective observational and Mendelian randomization studies.
Frontiers in endocrinology
Purpose:Cortisol has obesogenic, hyperglycemic and immunomodulating effects. Preclinical and observational research suggested that it is associated with periodontitis but the evidence for potential causality in humans is sparse. We triangulated results from prospective observational and Mendelian randomization (MR) analyses to further explore this. Methods:Using pooled data from 3,388 participants of two population cohort studies embedded in the Study of Health in Pomerania (SHIP) project, we associated serum cortisol levels with periodontal outcomes measured after a median follow-up time of 6.9 years, adjusting for confounding and selection bias using propensity score weighting and multiple imputation. We further examined the effect of genetically proxied plasma morning cortisol levels on periodontitis using two-sample MR of 17,353 cases and 28,210 controls. Results:In SHIP, we found that cortisol levels were positively associated with follow-up levels of mean clinical attachment level (CAL), deep interdental CAL and bleeding on probing but were unrelated to mean probing pocket depth and deep periodontal pockets. In MR analysis, cortisol was not associated with periodontitis. Conclusion:The observational study revealed a prospective association of spot cortisol with makers of periodontitis. Contrary to observational studies, genetically instrumented, long-term cortisol was unrelated to periodontitis. Our results find no univocal evidence that cortisol plays a role in periodontitis pathology, casting doubt on cortisol-related pathways.
10.3389/fendo.2023.1100985
Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data.
Nature genetics
Single-cell RNA sequencing (scRNA-seq) provides unique insights into the pathology and cellular origin of disease. We introduce single-cell disease relevance score (scDRS), an approach that links scRNA-seq with polygenic disease risk at single-cell resolution, independent of annotated cell types. scDRS identifies cells exhibiting excess expression across disease-associated genes implicated by genome-wide association studies (GWASs). We applied scDRS to 74 diseases/traits and 1.3 million single-cell gene-expression profiles across 31 tissues/organs. Cell-type-level results broadly recapitulated known cell-type-disease associations. Individual-cell-level results identified subpopulations of disease-associated cells not captured by existing cell-type labels, including T cell subpopulations associated with inflammatory bowel disease, partially characterized by their effector-like states; neuron subpopulations associated with schizophrenia, partially characterized by their spatial locations; and hepatocyte subpopulations associated with triglyceride levels, partially characterized by their higher ploidy levels. Genes whose expression was correlated with the scDRS score across cells (reflecting coexpression with GWAS disease-associated genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.
10.1038/s41588-022-01167-z
Genome-wide association studies identify the role of caspase-9 in kidney disease.
Science advances
Genome-wide association studies (GWAS) have identified hundreds of genetic risk regions for kidney dysfunction [estimated glomerular filtration rate (eGFR)]; however, the causal genes, cell types, and pathways are poorly understood. Integration of GWAS and human kidney expression of quantitative trait analysis using Bayesian colocations, transcriptome-wide association studies, and summary-based Mendelian randomization studies prioritized caspase-9 (CASP9) as a kidney disease risk gene. Human kidney single-cell epigenetic and immunostaining studies indicated kidney tubule cells as a disease-causing cell type. Mice with genetic deletion or pharmacological inhibition of CASP9 showed lower apoptosis while having improved mitophagy, resulting in dampened activation of cytosolic nucleotide sensing pathways (cGAS-STING), reduction of inflammation, and protection from acute kidney disease or renal fibrosis. In summary, here, we prioritized CASP9 as an eGFR GWAS target gene and demonstrated the causal role of CASP9 in kidney disease development via improving mitophagy and lowering inflammation and apoptosis.
10.1126/sciadv.abi8051
Effects of a Parenting Intervention for Emotional and Behavioral Problems in Young Autistic Children Under Conditions of Enhanced Uncertainty: Two-Year Follow-up of a Pilot Randomized Controlled Trial Cohort (ASTAR) During the United Kingdom COVID-19 Pandemic.
Journal of the American Academy of Child and Adolescent Psychiatry
OBJECTIVE:Most young autistic children display emotional and behavioral problems (EBPs). There is evidence that behavioral parenting interventions (BPIs) reduce these. The COVID-19 pandemic and associated lockdowns can be seen as a natural experiment to test the longer-term effect of BPIs under conditions of increased uncertainty. METHOD:Opportunistic follow-up (n = 49) of a pilot randomized controlled trial (RCT) cohort (n = 62 autistic children aged 6-11 years; originally randomized to a 12-week group BPI [Predictive Parenting; n = 31] or an attention control [Psychoeducation; n = 31]) was conducted during COVID-19-related lockdowns. Measures of parent-reported child irritability and parenting stress were collected at 3 time points (baseline: mean age = 6.7 years; primary endpoint: mean age = 7.1 years, ∼5 months after randomization; and COVID-19 follow-up: mean age = 8.8 years, ∼2 years after randomization). We tested the magnitude of intervention effects using point estimates of differences in child irritability and parenting stress between arms at primary endpoint and COVID-19 follow-up, covarying for baseline scores. We used area under the curve (AUC) analyses to obtain overall estimates of the average intervention effect across all 3 timepoints. Semi-structured qualitative interviews were conducted with a subsample of parents (n = 18). RESULTS:A small but significant intervention effect was found from baseline to COVID-19 follow-up in favor of Predictive Parenting on parent-reported child irritability (d = -0.33, 95% CI = -0.65, -0.01) and parenting stress (d = -0.31, 95% CI = -0.59, -0.03). No overall mean intervention effect for these measures as estimated by the AUC analyses (which takes into account the nonsignificant effect at primary endpoint) was found. Interview feedback on the both interventions was positive, and parents reported using strategies from Predictive Parenting during COVID-19-related restrictions. CONCLUSION:This opportunistic follow-up study at a time of stress indicates the need for careful consideration of how and when to measure the effects of BPIs in autistic child populations. Future trials should consider both the most appropriate endpoint and in what context effects may be more likely to be seen. CLINICAL TRIAL REGISTRATION INFORMATION:Autism Spectrum Treatment and Resilience (ASTAR); https://www.isrctn.com; 91411078.
10.1016/j.jaac.2022.09.436
Causal associations of sleep apnea and snoring with type 2 diabetes and glycemic traits and the role of BMI.
Obesity (Silver Spring, Md.)
OBJECTIVE:Sleep apnea and snoring have been associated with type 2 diabetes, with BMI playing a role in the pathway, but the directions of causality are unclear. This study examined the causal associations of sleep apnea and snoring with type 2 diabetes while assessing the role of BMI using multiple genetic methods. METHODS:Five genetic methods were used: two-sample; bidirectional univariable Mendelian randomization (MR) inverse variance-weighted (MR-IVW); multivariable MR-IVW; network MR; and latent causal variable method. RESULTS:Compared with univariable MR-IVW, the odds ratio (95% CI) of type 2 diabetes for genetically predicted sleep apnea and snoring using the largest genome-wide association study decreased dramatically, from 1.61 (95% CI: 1.16-2.23) to 1.08 (95% CI: 0.59-1.97) and from 1.98 (95% CI: 1.25-3.13) to 1.09 (95% CI: 0.64-1.86) after adjustment for BMI. Network MR showed that BMI accounts for 67% and 62% of the total effect of sleep apnea and snoring on type 2 diabetes, respectively. The latent causal variable suggested that sleep apnea and snoring have no direct causal effect on type 2 diabetes. CONCLUSIONS:These results first suggest that the associations of sleep apnea and snoring with type 2 diabetes were mainly driven by BMI. The possible indirect effects of sleep apnea and snoring on type 2 diabetes through BMI cannot be ruled out.
10.1002/oby.23669
Causal associations between dried fruit intake and cardiovascular disease: A Mendelian randomization study.
Frontiers in cardiovascular medicine
Background:Previous studies have shown controversy about whether dried fruit intake is associated with cardiovascular disease. This study aimed to examine the potential causal effect of dried fruit intake on cardiovascular disease by conducting a two-sample Mendelian randomization study. Methods:We used genome-wide association study (GWAS) summary statistics for MR analysis to explore the causal association of dried fruit intake with CVD. The inverse-variance weighted (IVW) method was used as the main analytical method for MR analysis. In addition, the MR-Egger method and the weighted median method were applied to supplement the IVW method. Furthermore, Cochrane's test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were used to perform sensitivity analysis. Results:The results from the IVW analysis indicated that dried fruit intake could reduce the risk of heart failure [odds ratio (OR) = 0.6014, 95% confidence interval (CI): 0.4243-0.8522, -value = 0.0043], total ischemic stroke (OR = 0.4547, 95% CI: 0.2950-0.7010, -value = 0.0004), and small vessel stroke (OR = 0.3499, 95% CI: 0.1466-0.8349, -value = 0.0180). In addition, the results of two additional methods (MR Egger and Weighted median) were parallel to the effects estimated by IVW. Furthermore, the sensitivity analysis illustrates that our MR analysis was unaffected by heterogeneity and horizontal pleiotropy. Finally, the results of the leave-one-out method showed the robustness of our MR results. Conclusion:Our study provides evidence for the benefits of dried fruit intake on CVD. Therefore a reasonable consumption of dried fruit may provide primary prevention.
10.3389/fcvm.2023.1080252
Obesity and risk of gestational diabetes mellitus: A two-sample Mendelian randomization study.
Diabetes research and clinical practice
AIMS:To estimate genetically predicted causal associations of general and central obesity with GDM, and to determine the mediating role of circulating lipids. METHODS:Summary-level data was obtained from the largest available genome-wide association studies of five obesity traits, five lipid traits and GDM. Two-sample univariate Mendelian randomization (MR), multivariate MR, and MR-based mediation analysis was applied to determine the total effect, direct effect and the mediating effect, respectively. RESULTS:Univariate MR showed that the odds of GDM increased per 1-SD increase in body mass index (BMI) (OR = 1.64, P = 5.05 × 10), waist-to-hip ratio (WHR) (OR = 1.57, P = 2.27 × 10) and WHR adjusted for BMI (OR = 1.42, P = 6.11 × 10). The heterogeneous associations of waist circumference (OR = 1.64, P = 5.57 × 10) and hip circumference (OR = 1.20, P = 0.002) on GDM further reflected that body fat distribution could influence GDM risk. Mediation analysis suggested that triglycerides, high-density lipoprotein-cholesterol and apolipoprotein A-I each mediated between 5% and 10% of the association between obesity and GDM. CONCLUSION:Our findings supported a deleterious causal effect of obesity on GDM risk, where lipid metabolism acted as potential drivers of the relationships between both general and central obesity and GDM.
10.1016/j.diabres.2023.110561
Body mass index, C-reactive protein, and pancreatic cancer: A Mendelian randomization analysis to investigate causal pathways.
Frontiers in oncology
Aim:To explore whether C-reactive protein (CRP) mediates the risk of body mass index (BMI) in pancreatic cancer (PC) and calculate the mediate proportion of CRP in this possible mechanism. Methods:Based on two-sample Mendelian randomization (TSMR), a two-step Mendelian randomization (TM) model was conducted to determine whether CRP was a mediator of the causal relationship between BMI and PC. The multivariable Mendelian randomization (MVMR) study was designed for mediating analysis and to calculate the mediating proportion mediated by CRP. Results:BMI has a positive causal relationship with PC (n = 393 SNPs, OR = 1.484, 95% CI: 1.021-2.157, p< 0.05). BMI has a positive causal relationship with CRP (n = 179 SNPs, OR = 1.393, 95% CI: 1.320-1.469, p< 0.05). CRP has a positive causal relationship with PC (n = 54 SNPs, OR = 1.348, 95% CI: 1.004-1.809, p 0.05). After adjusting CRP, BMI has no causal relationship with PC (n = 334 SNPs, OR = 1.341, 95% CI: 0.884-2.037, p< 0.05). After adjusting BMI, there was still a positive causal relationship between CRP and PC (n = 334 SNPs, OR = 1.441, 95% CI: 1.064-1.950, p< 0.05). The mediating effect of CRP was 29%. Conclusions:In clinical practice, while actively advocating for weight loss among obese patients, we should focus on chronic inflammation levels in obese patients as well. In addition, anti-inflammatory dietary patterns and appropriate physical activity are important in preventing PC.
10.3389/fonc.2023.1042567
Plasma protein and venous thromboembolism: prospective cohort and mendelian randomisation analyses.
British journal of haematology
We conducted cohort and Mendelian randomisation (MR) analyses to examine the associations of circulating proteins with risk of venous thromboembolism (VTE) to provide evidence basis for disease prevention and drug development. Cohort analysis was performed in 11 803 participants without baseline VTE. Cox regression was used to estimate the associations between 257 proteins and VTE risk. A machine-learning model was constructed to compare the importance of identified proteins and traditional risk factors. Genetic association data on VTE were obtained from a genome-wide meta-analysis (26 066 cases and 624 053 controls) and FinnGen (14 454 cases and 294 700 controls). The cohort analysis, including 353 incident VTE cases diagnosed during a 6.6-year follow-up, identified 21 proteins associated with VTE risk after false discovery rate correction. The machine-learning model indicated that body mass index and von Willebrand factor (vWF) made the same as well as most of the contributions to the overall model prediction. MR analysis found that genetically predicted levels of vWF, SERPINE1 (plasminogen activator inhibitor 1, known as PAI-1), EPHB4 (ephrin type-B receptor 4), TYRO3 (tyrosine-protein kinase receptor TYRO3), TNFRSF11A (tumour necrosis factor receptor superfamily member 11A), and BOC (brother of CDO) were causally associated with VTE risk.
10.1111/bjh.18679
Potential therapeutic targets for sarcopenia identified by Mendelian randomisation.
Age and ageing
BACKGROUND:Identifying sarcopenia's causally associated plasma proteins would provide potential therapeutic targets. METHODS:We screened out sarcopenia-related proteins with genome-wide association studies (GWAS) summary data and cis-protein loci genetic instruments. Summary data of sarcopenia were obtained from a GWAS of 256,523 Europeans aged 60 years and over. The causal effects of the proteins were investigated by cis-Mendelian Randomisation (MR) and multiverse sensitivity analysis. We also explored the robust proteins' causal associations with appendicular lean mass (ALM) and surveyed their druggability and clinical development activities. RESULTS:In sum, 60 proteins from plasma proteome analysis studies and 12 from other studies were enrolled for MR analysis. In the whole population, four proteins (HPT, AT1B2, ISLR2 and TNF12) showed causal associations with the risk of sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP) criterion. In the female population, AT1B2 and TNFSF12 revealed causal associations with sarcopenia risk according to the EWGSOP criterion; HGF revealed a negative association according to the National Institutes of Health criterion. All of them were druggable, and the inhibitors of TNF12 and HGF were evaluated in clinical trials for other diseases. TNF12 also revealed a negative causal association with ALM, whereas HGF was positively causally associated with ALM. CONCLUSIONS:Five druggable plasma proteins revealed causal associations with sarcopenia in the whole or female populations. TNF12 and HGF were the targets of therapeutic agents evaluated in clinical trials, and they were also causally associated with ALM. Our study suggested the potential mechanisms and therapeutic targets for sarcopenia.
10.1093/ageing/afad024
Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.
Nature communications
Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease.
10.1038/s41467-022-35663-x
The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomisation study.
BMC medicine
BACKGROUND:Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference. METHODS:Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings. RESULTS:The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results. CONCLUSIONS:Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.
10.1186/s12916-023-02731-y
Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis.
Gastroenterology
BACKGROUND & AIMS:Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. METHODS:We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708). RESULTS:The meta-analysis identified genome-wide significant variants (P <5 × 10) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. CONCLUSIONS:This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP.
10.1053/j.gastro.2023.01.028
Association between trans fatty acids and COVID-19: A multivariate Mendelian randomization study.
Journal of medical virology
Traditional observational studies have suggested a potential association between trans fatty acids (TFAs), which are considered to be health-damaging fatty acids, and coronavirus disease 2019 (COVID-19). However, whether there is a causal relationship between them is currently unclear. We aimed to investigate the causal link between genetically determined TFAs and COVID-19. We performed univariate and multivariate Mendelian randomization (MR) studies using summary statistics from the European Pedigree TFAs (n = 8013), COVID-19 susceptibility (n = 159 840), COVID-19 hospitalization (n = 44 986), and COVID-19 severity (n = 18 152) genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary MR analysis, and several other methods were used as supplements. In univariate MR analysis, higher levels of circulating trans, cis-18:2 TFAs were positively associated with a higher COVID-19 hospitalization rate (p < 0.0033; odds ratio [OR] = 1.637; 95% confidence interval [CI]: 1.116-2.401) and COVID-19 severity (p < 0.0033; OR = 2.575; 95% CI: 1.412-4.698). Furthermore, in multivariate MR analysis, trans, cis-18:2 had an independent and significant causal association with a higher COVID-19 hospitalization rate (p = 0.00044; OR = 1.862; 95% CI = 1.316-2.636) and COVID-19 severity (p = 0.0016; OR = 2.268; 95% CI = 1.361-3.779) after the five TFAs were adjusted for each other. Together, our findings provide evidence that trans, cis-18:2 TFAs have an independent and robust causal effect on COVID-19 hospitalization and severity.
10.1002/jmv.28455
Association between sleep duration and metabolic syndrome: linear and nonlinear Mendelian randomization analyses.
Journal of translational medicine
BACKGROUND:Observational studies have found that both short and long sleep duration are associated with increased risk of metabolic syndrome (MetS). This study aimed to examine the associations of genetically determined sleep durations with MetS and its five components (i.e., central obesity, high blood pressure, dyslipidemia, hypertriglyceridemia, and hyperglycemia) among a group of elderly population. METHODS:In 335,727 participants of White British from the UK Biobank, linear Mendelian randomization (MR) methods were first employed to examine the causal association of genetically predicted continuous sleep duration with MetS and its each component. Nonlinear MR analyses were performed to determine the nonlinearity of these associations. The causal associations of short and long sleep duration with MetS and its components were further assessed by using genetic variants that associated with short (≤ 6 h) and long sleep (≥ 9 h) durations. RESULTS:Linear MR analyses demonstrated that genetically predicted 1-h longer sleep duration was associated with a 13% lower risk of MetS, a 30% lower risk of central obesity, and a 26% lower risk of hyperglycemia. Non-linear MR analyses provided evidence for non-linear associations of genetically predicted sleep duration with MetS and its five components (all P values < 0.008). Genetically predicted short sleep duration was moderately associated with MetS and its four components, including central obesity, dyslipidemia, hypertriglyceridemia, and hyperglycemia (all P values < 0.002), whereas genetically long sleep duration was not associated with MetS and any of its components. CONCLUSIONS:Genetically predicted short sleep duration, but not genetically predicted long sleep duration, is a potentially causal risk factor for MetS.
10.1186/s12967-023-03920-2
Vitamin D deficiency and C-reactive protein: a bidirectional Mendelian randomization study.
International journal of epidemiology
BACKGROUND:Low vitamin D status is often associated with systemic low-grade inflammation as reflected by elevated C-reactive protein (CRP) levels. We investigated the causality and direction of the association between vitamin D status and CRP using linear and non-linear Mendelian randomization (MR) analyses. METHODS:MR analyses were conducted using data from 294 970 unrelated participants of White-British ancestry from the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] and CRP concentrations were instrumented using 35 and 46 genome-wide significant variants, respectively. RESULTS:In non-linear MR analysis, genetically predicted serum 25(OH)D had an L-shaped association with serum CRP, where CRP levels decreased sharply with increasing 25(OH)D concentration for participants within the deficiency range (<25 nmol/L) and levelled off at ∼50 nmol/L of 25(OH)D (Pnon-linear = 1.49E-4). Analyses using several pleiotropy-robust methods provided consistent results in stratified MR analyses, confirming the inverse association between 25(OH)D and CRP in the deficiency range (P = 1.10E-05) but not with higher concentrations. Neither linear or non-linear MR analysis supported a causal effect of serum CRP level on 25(OH)D concentration (Plinear = 0.32 and Pnon-linear = 0.76). CONCLUSION:The observed association between 25(OH)D and CRP is likely to be caused by vitamin D deficiency. Correction of low vitamin D status may reduce chronic inflammation.
10.1093/ije/dyac087
Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.
International journal of epidemiology
BACKGROUND:Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. METHODS:Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. RESULTS:In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. CONCLUSIONS:These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.
10.1093/ije/dyac124
Mendelian randomization study of maternal coffee consumption and its influence on birthweight, stillbirth, miscarriage, gestational age and pre-term birth.
International journal of epidemiology
BACKGROUND:Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). METHODS:A two-sample MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis); the number of stillbirths [N = 60 453 from UK Biobank (UKBB)]; gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring's birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-sample genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. RESULTS:Both the two-sample MR and one-sample GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. CONCLUSION:Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.
10.1093/ije/dyac121
Reassessing the causal role of obesity in breast cancer susceptibility: a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure.
International journal of epidemiology
BACKGROUND:Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life. METHODS:Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation. RESULTS:In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7). CONCLUSION:Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.
10.1093/ije/dyac143
Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study.
International journal of epidemiology
BACKGROUND:Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. METHODS:We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768). RESULTS:Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: -50, 6); P = 0.13] and UKB [-28 g (95% CI: -31, -25); P = 1.8 × 10-75]. The MR causal effect estimate was directionally consistent, but smaller [-11 g (95% CI: -25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10-22], consistent with that previously published in women and men. CONCLUSION:The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
10.1093/ije/dyac186
Dietary precursors and cardiovascular disease: A Mendelian randomization study.
Frontiers in cardiovascular medicine
Background:The Dietary precursor has been identified as a contributor in the development of cardiovascular disease. However, it is inconsistent if dietary precursors could affect the process of cardiovascular disease. Methods:Here we performed Mendelian randomization (MR) analysis of the data from genome-wide association study of European ancestry to evaluate the independent effects of three dietary precursors on cardiovascular disease (CVD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and valvular disease (VHD). Inverse variance weighting method was used for the MR estimation. Sensitivity was determined by MR-PRESSO analysis, weighted median analysis, MR-Egger analysis, and Leave-one-out analysis. Results:We found that elevated choline level had a causal relationship with VHD [odds ratio (OR) = 1.087, 95% confidence interval (CI), 1.003-1.178, = 0.041] and MI (OR = 1.250, 95% CI, 1.041-1.501, = 0.017) by single-variable MR analysis. Furthermore, elevated carnitine level was associated with MI (OR = 5.007, 95% CI, 1.693-14.808, = 0.004) and HF (OR = 2.176, 95% CI, 1.252-3.780, = 0.006) risk. In addition, elevated phosphatidylcholine level can increase the risk of MI (OR = 1.197, 95% CI, 1.026-1.397, = 0.022). Conclusion:Our data show that choline increases VHD or MI risk, carnitine increases the risk of MI or HF, and phosphatidylcholine increases HF risk. These findings suggest the possibility that decrease in choline level in circulation may be able to reduce overall VHD or MI risk, reduce in carnitine level could be decrease MI and HF risks as well as decrease in phosphatidylcholine could reduce MI risk.
10.3389/fcvm.2023.1061119
Causal association between cardiovascular diseases and erectile dysfunction, a Mendelian randomization study.
Frontiers in cardiovascular medicine
Background:Cardiovascular diseases (CVD), including coronary heart disease (CHD), heart failure, ischemic heart disease (IHD), and atrial fibrillation, are prevalent in the aged. However, the influence of CVD on ED is less investigated. This study was performed to clarify the causal association between CVD and ED. Materials and methods:Genome-wide association studies (GWAS) datasets targeting CHD, heart failure, IHD, and atrial fibrillation were downloaded to retrieve single nucleotide polymorphisms (SNPs). Further, single-variable Mendelian randomization and multivariable Mendelian randomization (MVMR) were adopted to explore the causal association between CVD and ED. Results:Genetically predicted CHD and heart failure were found to increase the risks of ED (OR = 1.09, < 0.05 and OR = 1.36, < 0.05, respectively). However, no causal association was disclosed among IHD, atrial fibrillation and ED (all > 0.05). These findings remained consistent in sensitivity analyses. After controlling for body mass index, alcohol, low density lipoprotein, smoking and total cholesterol levels, the results of MVMR support the causal role of CHD on ED ( < 0.05). Similarly, the direct causal effect estimates of heart failure on ED were significant in MVMR analyses ( < 0.05). Conclusion:Using genetic data, this study revealed that genetically predicted CHD and heart failure may predict better ED compared with atrial fibrillation and IHD. The results should be interpreted with caution and the insignificant causal inference of IHD still needs further verification in future studies.
10.3389/fcvm.2023.1094330
Multisite chronic pain and the risk of autoimmune diseases: A Mendelian randomization study.
Frontiers in immunology
Background:Accumulating evidence has demonstrated that an association between chronic pain and autoimmune diseases (AIDs). Nevertheless, it is unclear whether these associations refer to a causal relationship. We used a two-sample Mendelian randomization (MR) method to determine the causal relationship between chronic pain and AIDs. Methods:We assessed genome-wide association study (GWAS) summary statistics for chronic pain [multisite chronic pain (MCP) and chronic widespread pain (CWP)], and eight common AIDs, namely, amyotrophic lateral sclerosis (ALS), celiac disease (CeD), inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), type 1 diabetes (T1D) and psoriasis. Summary statistics data were from publicly available and relatively large-scale GWAS meta-analyses to date. The two-sample MR analyses were first performed to identify the causal effect of chronic pain on AIDs. The two-step MR and multivariable MR were used to determine if mediators (BMI and smoking) causally mediated any connection and to estimate the proportion of the association mediated by these factors combined. Results:With the utilization of MR analysis, multisite chronic pain was associated with a higher risk of MS [odds ratio (OR) = 1.59, 95% confidence interval (CI) = 1.01-2.49, = 0.044] and RA (OR = 1.72, 95% CI = 1.06-2.77, = 0.028). However, multisite chronic pain had no significant effect on ALS (OR = 1.26, 95% CI = 0.92-1.71, = 0.150), CeD (OR = 0.24, 95% CI = 0.02-3.64, = 0.303), IBD (OR = 0.46, 95% CI = 0.09-2.27, = 0.338), SLE (OR = 1.78, 95% CI = 0.82-3.88, = 0.144), T1D (OR = 1.15, 95% CI = 0.65-2.02, = 0.627) or Psoriasis (OR = 1.59, 95% CI = 0.22-11.26, = 0.644). We also found positive causal effects of MCP on BMI and causal effects of BMI on MS and RA. Moreover, there were no causal connections between genetically predicted chronic widespread pain and the risk of most types of AIDs disease. Conclusion:Our MR analysis implied a causal relationship between MCP and MS/RA, and the effect of MCP on MS and RA may be partially mediated by BMI.
10.3389/fimmu.2023.1077088
Branched-chain amino acids and risk of stroke: A Mendelian randomization study.
Frontiers in neuroscience
Background:The causality between plasma branched-chain amino acids (BCAAs) levels and stroke remains uncertain and the stratified research on the association between BCAAs levels and subtypes of stroke is not well studied. Therefore, the association of genetically proxied circulating BCAA levels with the risks of stroke and its subtypes was explored by Mendelian randomization (MR) in this study. Methods:Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Data for plasma BCAA levels ( = 16,596) were obtained from a meta-analysis of GWAS. The MEGASTROKE consortium provided data for ischemic stroke ( = 440,328) and its subtypes and data for hemorrhagic stroke were available from 2 meta-analyses of GWAS of European-ancestry groups (intracerebral hemorrhage, = 3,026; subarachnoid hemorrhage, = 77,074). The inverse variance weighted (IVW) method was selected as the primary MR analysis. Supplementary analysis used included the weighted median, MR-Egger regression, Cochran's Q statistic, MR Pleiotropy Residual Sum and Outlier global test, and leave-one-out analysis method. Results:According to IVW analysis, 1-SD increment in genetically determined circulating isoleucine was associated with increased risks of cardioembolic stroke (CES) (OR: 1.56, 95% CI: 1.21-2.20, = 0.0007), but not with risks of other stroke subtypes. We could not discover any proof that leucine and valine levels could increase risk of any stroke subtype. All heterogeneity tests produced stable findings, and there was no concrete evidence to indicate the perturbation of horizontal multiplicity. Conclusion:Increasing plasma isoleucine level had a causal effect on the risk of CES but not on the risk of other stroke subtypes. Further research is needed to identify the mechanisms of the causal associations between BCAAs and stroke subtypes.
10.3389/fnins.2023.1143718
Mendelian randomization reveals no associations of genetically-predicted obstructive sleep apnea with the risk of type 2 diabetes, nonalcoholic fatty liver disease, and coronary heart disease.
Frontiers in psychiatry
Background:Obstructive sleep apnea (OSA) has been reported to affect cardiometabolic diseases. However, whether such association is causal is still unknown. Here, we attempt to explore the effect of OSA on type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD). Methods:Genetic variants associated with OSA were requested from a published genome-wide association study (GWAS) and those qualified ones were selected as instrumental variables (IV). Then, the IV-outcome associations were acquired from T2D, NAFLD and CHD GWAS consortia separately. The Mendelian randomization (MR) was designed to estimate the associations of genetically-predicted OSA on T2D, NAFLD and CHD respectively, using the inverse-variance weighted (IVW) method. We applied the Bonferroni method to adjust the p-value. Besides, MR-Egger regression and weighted median methods were adopted as a supplement to IVW. The Cochran's Q value was used to evaluate heterogeneity and the MR-Egger intercept was utilized to assess horizontal pleiotropy, together with MR-PRESSO. The leave-one-out sensitivity analysis was carried out as well. Results:No MR estimate reached the Bonferroni threshold ( < 0.017). Although the odds ratio of T2D was 3.58 (95% confidence interval (CI) [1.06, 12.11], IVW--value = 0.040) using 4 SNPs, such causal association turned insignificant after the removal of SNP rs9937053 located in FTO [OR = 1.30 [0.68, 2.50], IVW = 0.432]. Besides, we did not find that the predisposition to OSA was associated with CHD [OR = 1.16 [0.70, 1.91], IVW = 0.560] using 4 SNPs. Conclusion:This MR study reveals that genetic liability to OSA might not be associated with the risk of T2D after the removal of obesity-related instruments. Besides, no causal association was observed between NAFLD and CHD. Further studies should be carried out to verify our findings.
10.3389/fpsyt.2023.1068756
Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk.
International journal of cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is featured by systematic metabolism. Thus, a better understanding of metabolic dysregulation in PDAC is important to better characterize its etiology. Here, we performed a large metabolome-wide association study (MWAS) to systematically explore associations between genetically predicted metabolite levels in blood and PDAC risk. Using data from 881 subjects of European descent in the TwinsUK Project, comprehensive genetic models were built to predict serum metabolite levels. These prediction models were applied to the genetic data of 8275 cases and 6723 controls included in the PanScan (I, II and III) and PanC4 consortia. After assessing the metabolite-PDAC risk associations by a slightly modified TWAS/FUSION framework, we identified five metabolites (including two dipeptides) showing significant associations with PDAC risk at false discovery rate (FDR) <0.05. Integrated with gut microbial information, two-sample Mendelian randomization (MR) analyses were further performed to investigate the relationship among serum metabolites, gut microbiome features and PDAC. The flavonoid-degrading bacteria Flavonifractor sp90199495 was found to be associated with metabolite X-21849 and it was also shown to be associated with PDAC risk. Collectively, our study identified novel candidate metabolites for PDAC risk, which could lead to new insights into the etiology of PDAC and improved treatment options.
10.1002/ijc.34466
Phenome-wide genetic-correlation analysis and genetically informed causal inference of amyotrophic lateral sclerosis.
Human genetics
Leveraging genome-wide association statistics generated from a large study of amyotrophic lateral sclerosis (ALS; 29,612 cases and 122,656 controls) and UK Biobank (UKB; 4,024 phenotypes, up to 361,194 participants), we conducted a phenome-wide analysis of ALS genetic liability and identified 46 genetically correlated traits, such as fluid intelligence score (r = - 0.21, p = 1.74 × 10), "spending time in pub or social club" (r = 0.24, p = 2.77 × 10), non-work related walking (r = - 0.25, p = 1.95 × 10), college education (r = - 0.15, p = 7.08 × 10), "ever diagnosed with panic attacks (r = 0.39, p = 4.24 × 10), and "self-reported other gastritis including duodenitis" (r = 0.28, p = 1.4 × 10). To assess the putative directionality of these genetic correlations, we conducted a latent causal variable analysis, identifying significant genetic causality proportions (gĉp) linking ALS genetic liability to seven traits. While the genetic component of "self-reported other gastritis including duodenitis" showed a causal effect on ALS (gĉp = 0.50, p = 1.26 × 10), the genetic liability to ALS is potentially causal for multiple traits, also including an effect on "ever being diagnosed with panic attacks" (gĉp = 0.79, p = 5.011 × 10) and inverse effects on "other leisure/social group activities" (gĉp = 0.66, p = 1 × 10) and prospective memory result (gĉp = 0.35, p = 0.005). Our subsequent Mendelian randomization analysis indicated that some of these associations may be due to bidirectional effects. In conclusion, this phenome-wide investigation of ALS polygenic architecture highlights the widespread pleiotropy linking this disorder with several health domains.
10.1007/s00439-023-02525-5
Mendelian randomization study shows a causal effect of asthma on epilepsy risk.
Frontiers in immunology
Objective:The relationship between asthma and epilepsy in observational studies is controversial. The purpose of this Mendelian randomization (MR) study is to investigate whether asthma causally contributes to epilepsy susceptibility. Methods:Independent genetic variants strongly (P<5E-08) associated with asthma were from a recent meta-analysis of genome-wide association studies on 408,442 participants. Two independent summary statistics of epilepsy obtained from the International League Against Epilepsy Consortium (ILAEC, Ncases=15,212, and Ncontrols=29,677) and FinnGen Consortium (Ncases=6,260 and Ncontrols=176,107) were used in the discovery and replication stage, respectively. Several sensitivity analyses and heterogeneity analyses were further conducted to assess the stability of the estimates. Results:Using the inverse-variance weighted approach, genetic predisposition to asthma was associated with an elevated risk of epilepsy in the discovery stage (ILAEC: odds ratio [OR]=1.112, 95% confidence intervals [CI]= 1.023-1.209, = 0.012), but not verified in the replication stage (FinnGen: OR=1.021, 95%CI= 0.896-1.163, =0.753). However, a further meta-analysis of both ILAEC and FinnGen showed a similar result (OR=1.085, 95% CI: 1.012-1.164, = 0.022). There were no causal associations between the age onset of asthma and epilepsy. Sensitivity analyses yielded consistent causal estimates. Conclusion:The present MR study suggests that asthma is associated with an increased risk of epilepsy independent of the age onset of asthma. Further studies are warranted to explain the underlying mechanisms of this association.
10.3389/fimmu.2023.1071580
Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling.
European journal of human genetics : EJHG
Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.
10.1038/s41431-021-00933-7
Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure.
European heart journal
BACKGROUND AND AIMS:Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. METHODS AND RESULTS:Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI) -0.066, -0.021] with the MR estimate strengthening (-0.087 SD; 95% CI -0.132, -0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule. CONCLUSION:Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance.
10.1093/eurheartj/ehad101
Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.
Nutrients
Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
10.3390/nu13114164
The genetic liability to rheumatoid arthritis may decrease hepatocellular carcinoma risk in East Asian population: a Mendelian randomization study.
Arthritis research & therapy
BACKGROUND:Patients with rheumatoid arthritis (RA) have a rising possibility of acquiring certain kinds of cancers than the general public. The causal risk association between RA and hepatocellular carcinoma (HCC) remains unknown. METHODS:Genetic summary data from genome-wide association study (GWAS), including RA (n = 19,190) and HCC (n = 197,611), was analyzed. The inverse-variance weighted (IVW) approach was used as the principal analysis, complemented with weighted median, weighted mode, simple median method, and MR-Egger analyses. The genetic data of RA (n = 212,453) was used to verify the results in eastern Asia populations. RESULTS:The results from the IVW methods indicated that genetically predicted RA was significantly linked with a declined possibility of HCC for East Asians (OR = 0.86; 95% CI: 0.78, 0.95; p = 0.003). The weighted median and the weighted mode also supported similar results (all p < 0.05). Additionally, neither the funnel plots nor the MR-Egger intercepts revealed any directional pleiotropic effects between RA and HCC. Moreover, the other set of RA data validated the results. CONCLUSION:The RA may decrease the risk of being susceptible to the HCC in eastern Asia populations, which was beyond expectation. In the future, additional investigations should be made into potential biomedical mechanisms.
10.1186/s13075-023-03029-3
Mendelian Randomization Analysis Provides Insights into the Pathogenesis of Serum Levels of Branched-Chain Amino Acids in Cardiovascular Disease.
Metabolites
Several observational studies have indicated an association between high serum levels of branched-chain amino acids (BCAAs) and an increased risk of cardiovascular disease (CVD). To assess whether theses associations reflect causality, we carried out two-sample Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with BCAA were evaluated in 10 studies, including 24,925 participants. The association between SNPs and coronary artery disease (CAD) were assessed using summary estimates from the CARDIoGRAMplusC4D consortium. Further MR analysis of BCAAs and seven CVD outcomes was performed. The BCAA-raising gene functions were also analyzed. MR analyses revealed a risk-increasing causal relationship between serum BCAA concentrations and CAD (odds ratio 1.08; 95% confidence interval (CI) 1.02-1.14), which was partly mediated by blood pressure and type 2 diabetes. BCAA also demonstrated a causal relationship with ischemic CVD events induced by plaque rupture and thrombosis (false discovery rate <0.05). Two BCAA-raising genes ( and ) were preferentially associated with myocardial infarction risk in the presence of atherosclerosis ( < 0.003). Functional analysis of the BCAA-raising genes suggested the causal involvement of two pathophysiological pathways, including glucose metabolism ( and ) related to plaque progression, and the newly discovered neuroendocrine disorders regulating blood pressure (, , and ) related to plaque rupture and thrombosis. This comprehensive MR analysis provided insights into the potential causal mechanisms linking BCAA with CVD risk and suggested targeting neuroendocrine disorders as a potential strategy for the prevention of CVD. These results warrant further studies to elucidate the mechanisms underlying these reported causal associations.
10.3390/metabo13030403
Genetic Causal Association between Iron Status and Osteoarthritis: A Two-Sample Mendelian Randomization.
Nutrients
Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA.
10.3390/nu14183683
Instant Coffee Is Negatively Associated with Telomere Length: Finding from Observational and Mendelian Randomization Analyses of UK Biobank.
Nutrients
Telomere length, as a biomarker of accelerated aging, is closely related to many chronic diseases. We aimed to explore the association between coffee consumption and telomere length. Our study included 468,924 participants from the UK Biobank. Multivariate linear models (observational analyses) were conducted to evaluate the associations of coffee intake, instant coffee intake, and filtered coffee intake with telomere length. In addition, we evaluated the causality of these associations in Mendelian randomization (MR) analyses by four methods (inverse-variance weighted (IVW), MR pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, and weighted median). Observational analyses indicated that coffee intake and instant coffee intake were negatively correlated with telomere length, which was equal to 0.12 year of age-related decrease in telomere length for each additional cup of coffee intake ( < 0.001), and 0.38 year of age-related decrease in telomere length for each additional cup of instant coffee intake ( < 0.001), respectively. There was no significant correlation between filtered coffee and telomere length ( = 0.862). Mendelian randomization analyses supported the results of observational analyses. Coffee intake was found to have a causal effect on telomere length through weighted median analysis ( = 0.022), and instant coffee intake had a causal effect on telomere length through IVW analysis ( = 0.019) and MR-PRESSO analysis ( = 0.028). No causal relationship was found between filtered coffee intake and telomere length ( > 0.05). Coffee intake, particularly instant coffee, was found to have an important role in shortening telomere length.
10.3390/nu15061354
Fatty acids and risk of dilated cardiomyopathy: A two-sample Mendelian randomization study.
Frontiers in nutrition
Background:Previous observational studies have shown intimate associations between fatty acids (FAs) and dilated cardiomyopathy (DCM). However, due to the confounding factors and reverse causal association found in observational epidemiological studies, the etiological explanation is not credible. Objective:To exclude possible confounding factors and reverse causal associations found in observational epidemiological studies, we used the two-sample Mendelian randomization (MR) analysis to verify the causal relationship between FAs and DCM risk. Method:All data of 54 FAs were downloaded from the genome-wide association studies (GWAS) catalog, and the summary statistics of DCM were extracted from the HF Molecular Epidemiology for Therapeutic Targets Consortium GWAS. Two-sample MR analysis was conducted to evaluate the causal effect of FAs on DCM risk through several analytical methods, including MR-Egger, inverse variance weighting (IVW), maximum likelihood, weighted median estimator (WME), and the MR pleiotropy residual sum and outlier test (MRPRESSO). Directionality tests using MR-Steiger to assess the possibility of reverse causation. Results:Our analysis identified two FAs, oleic acid and fatty acid (18:1)-OH, that may have a significant causal effect on DCM. MR analyses indicated that oleic acid was suggestively associated with a heightened risk of DCM (OR = 1.291, 95%CI: 1.044-1.595, = 0.018). As a probable metabolite of oleic acid, fatty acid (18:1)-OH has a suggestive association with a lower risk of DCM (OR = 0.402, 95%CI: 0.167-0.966, = 0.041). The results of the directionality test suggested that there was no reverse causality between exposure and outcome ( < 0.001). In contrast, the other 52 available FAs were discovered to have no significant causal relationships with DCM ( > 0.05). Conclusion:Our findings propose that oleic acid and fatty acid (18:1)-OH may have causal relationships with DCM, indicating that the risk of DCM from oleic acid may be decreased by encouraging the conversion of oleic acid to fatty acid (18:1)-OH.
10.3389/fnut.2023.1068050
Exploring the causal effects of the gut microbiome on serum lipid levels: A two-sample Mendelian randomization analysis.
Frontiers in microbiology
Background:The gut microbiome was reported to be associated with dyslipidemia in previous observational studies. However, whether the composition of the gut microbiome has a causal effect on serum lipid levels remains unclear. Objective:A two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationships between gut microbial taxa and serum lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and log-transformed triglyceride (TG) levels. Materials and methods:Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and four blood lipid traits were obtained from public datasets. Five recognized MR methods were applied to assess the causal estimates, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. Results:The combined results from the five MR methods and sensitivity analysis showed 59 suggestive causal associations and four significant causal associations. In particular, genus was associated with higher LDL-C ( = 3.01 × 10) and TC levels ( = 2.11 × 10), phylum was correlated with higher LDL-C level ( = 4.10 × 10), and genus was associated with lower TG level ( = 2.19 × 10). Conclusion:This research may provide novel insights into the causal relationships of the gut microbiome on serum lipid levels and new therapeutic or prevention strategies for dyslipidemia.
10.3389/fmicb.2023.1113334
Serum 25-Hydroxyvitamin D Levels and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study.
Nutrients
Observational studies have linked vitamin D insufficiency to pediatric type 2 diabetes (T2D), but evidence from vitamin D supplementation trials is sparse. Given the rising prevalence of pediatric T2D in all ethnicities, determining the protective role of vitamin D has significant public health importance. We tested whether serum 25-hydroxyvitamin D (25OHD) levels are causally linked to youth-onset T2D risk using Mendelian randomization (MR). We selected 54 single-nucleotide polymorphisms (SNPs) associated with 25OHD in a European genome-wide association study (GWAS) on 443,734 individuals and obtained their effects on pediatric T2D from the multi-ethnic PRODIGY GWAS (3006 cases/6061 controls). We applied inverse variance weighted (IVW) MR and a series of MR methods to control for pleiotropy. We undertook sensitivity analyses in ethnic sub-cohorts of PRODIGY, using SNPs in core vitamin D genes or ancestry-informed 25OHD SNPs. Multivariable MR accounted for the mediating effects of body mass index. We found that a standard deviation increase in 25OHD in the logarithmic scale did not affect youth-onset T2D risk (IVW MR odds ratio (OR) = 1.04, 95% CI = 0.96-1.13, = 0.35) in the multi-ethnic analysis, and sensitivity, ancestry-specific and multivariable MR analyses showed consistent results. Our study had limited power to detect small/moderate effects of 25OHD (OR of pediatric T2D < 1.39 to 2.1). In conclusion, 25OHD levels are unlikely to have significant effects on the risk of youth-onset T2D across different ethnicities.
10.3390/nu15041016
Gut microbiome and risk of ischaemic stroke: a comprehensive Mendelian randomization study.
European journal of preventive cardiology
AIMS:Increasing evidence implicates the microbiome as a susceptibility factor for ischaemic stroke (IS). Interpretation of this evidence is difficult, for the composition of the microbiome is influenced by various factors and might affect differently in IS subtypes. We aim to determine if the specific gut microbiome is causally associated with IS subtypes and suggest potential approaches for stroke prevention. METHODS AND RESULTS:We conducted a two-sample Mendelian randomization (MR) analysis to test the causal relationship between gut microbiome and IS subtypes. For exposure data, we extracted genetic variants associated with 194 bacterial traits from MiBioGen consortium (n = 18 340). For outcomes, we selected three IS subtypes including cardioembolic stroke (CES, n = 410 484), small vessel stroke (SVS, n = 198 048), and large artery stroke (LAS, n = 198 048). Additionally, we performed a sequence of sensitivity analyses to validate preliminary MR results. There were four, three, and four bacteria showing an increased risk for LAS, SVS, and CES, respectively, and there were five, six, and five bacteria leading a decreasing risk for LAS, SVS, and CES, respectively. Amongst these, the genus_Intestinimonas showed negative associations with LAS [odds ratio (OR) = 0.77, 95% confidence interval (CI) (0.61-0.98)] and SVS (0.85, 0.73-0.98). The genus_LachnospiraceaeNK4A136group was genetically associated with decreased risk of both SVS (0.81, 0.66-0.99) and CES (0.75, 0.60-0.94). CONCLUSION:The study revealed the causal effect of the abundance of specific bacterial features on the risk of IS subtypes. Notably, genus_Intestinimonas and genus_LachnospiraceaeNK4A136group displayed significant protection against more than one IS subtype, further suggesting potential applications of targeted probiotics in IS prevention.
10.1093/eurjpc/zwad052
Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.
Circulation
BACKGROUND:Calcific aortic stenosis (CAS) is the most common valvular heart disease in older adults and has no effective preventive therapies. Genome-wide association studies (GWAS) can identify genes influencing disease and may help prioritize therapeutic targets for CAS. METHODS:We performed a GWAS and gene association study of 14 451 patients with CAS and 398 544 controls in the Million Veteran Program. Replication was performed in the Million Veteran Program, Penn Medicine Biobank, Mass General Brigham Biobank, BioVU, and BioMe, totaling 12 889 cases and 348 094 controls. Causal genes were prioritized from genome-wide significant variants using polygenic priority score gene localization, expression quantitative trait locus colocalization, and nearest gene methods. CAS genetic architecture was compared with that of atherosclerotic cardiovascular disease. Causal inference for cardiometabolic biomarkers in CAS was performed using Mendelian randomization and genome-wide significant loci were characterized further through phenome-wide association study. RESULTS:We identified 23 genome-wide significant lead variants in our GWAS representing 17 unique genomic regions. Of the 23 lead variants, 14 were significant in replication, representing 11 unique genomic regions. Five replicated genomic regions were previously known risk loci for CAS () and 6 were novel (). Two novel lead variants were associated in non-White individuals (<0.05): rs12740374 () in Black and Hispanic individuals and rs1522387 () in Black individuals. Of the 14 replicated lead variants, only 2 (rs10455872 [], rs12740374 []) were also significant in atherosclerotic cardiovascular disease GWAS. In Mendelian randomization, lipoprotein(a) and low-density lipoprotein cholesterol were both associated with CAS, but the association between low-density lipoprotein cholesterol and CAS was attenuated when adjusting for lipoprotein(a). Phenome-wide association study highlighted varying degrees of pleiotropy, including between CAS and obesity at the locus. However, the locus remained associated with CAS after adjusting for body mass index and maintained a significant independent effect on CAS in mediation analysis. CONCLUSIONS:We performed a multiancestry GWAS in CAS and identified 6 novel genomic regions in the disease. Secondary analyses highlighted the roles of lipid metabolism, inflammation, cellular senescence, and adiposity in the pathobiology of CAS and clarified the shared and differential genetic architectures of CAS with atherosclerotic cardiovascular diseases.
10.1161/CIRCULATIONAHA.122.061451
Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.
Nature metabolism
Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.
10.1038/s42255-023-00742-w
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
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
A large-scale causal analysis of gut microbiota and delirium: A Mendelian randomization study.
Journal of affective disorders
BACKGROUND:Several studies have linked gut microbiota to human brain activity. This study used Mendelian randomization (MR) to investigate the causal relationship between gut microbes and delirium. METHODS:MR was used to select SNPs from large-scale GWAS summary data on 211 gut microbiota taxa and delirium. Inverse variance weighting (IVW), weighted median, and MR-Egger methods were used for statistical analyses. Outliers were assessed using the leave-one-out method. To avoid horizontal pleiotropy, we performed the MR-PRESSO and MR-Egger intercept tests. Cochran's Q and I values for IVW and MR-Egger were used to assess heterogeneity. RESULTS:IVW suggested that genetic prediction of the family Desulfovibrionaceae (1.784 (1.267-2.512), P = 0.001), order Desulfovibrionales (1.501 (1.058-2.128), P = 0.023), and genus Candidatus Soleaferrea (1.322 (1.052-1.659), P = 0.016) increased the risk of delirium, but the family Oxalobacteraceae (0.841 (0.722-0.981), P = 0.027), and genera Holdemania (0.766 (0.620-0.946), P = 0.013), Ruminococcus gnavus (0.806 (0.661-0.982), P = 0.033), and Eggerthella (0.815 (0.667-0.997), P = 0.047) reduced the risk of delirium. LIMITATIONS:(1) Limited sample size, (2) inability to assess gut microbiota interactions, and (3) limited to European populations. CONCLUSION:Our results suggest that presence of the microbial family Desulfovibrionaceae, order Desulfovibrionales, and genus Candidatus Soleaferrea increased the risk of delirium, whereas the Oxalobacteraceae family, and the genera Holdemania, Ruminococcus gnavus, and Eggerthella decreased the risk of delirium. However, the potential of gut probiotic interventions in the prevention of perioperative delirium should be emphasized.
10.1016/j.jad.2023.02.078
Association between Dietary Habits and Pancreatitis among Individuals of European Ancestry: A Two-Sample Mendelian Randomization Study.
Nutrients
Dietary factors are believed to potentially influence the risk of pancreatitis. Here, we systematically investigated the causal relationships between dietary habits and pancreatitis by using two-sample Mendelian randomization (MR). Large-scale genome-wide association study (GWAS) summary statistics for dietary habits were obtained from the UK Biobank. GWAS data for acute pancreatitis (AP), chronic pancreatitis (CP), alcohol-induced AP (AAP) and alcohol-induced CP (ACP) were from the FinnGen consortium. We performed univariable and multivariable MR analyses to evaluate the causal association between dietary habits and pancreatitis. Genetically driven alcohol drinking was associated with increased odds of AP, CP, AAP and ACP (all with < 0.05). Genetic predisposition to higher dried fruit intake was associated with reduced risk of AP (OR = 0.280, = 1.909 × 10) and CP (OR = 0.361, = 0.009), while genetic predisposition to fresh fruit intake was associated with reduced risk of AP (OR = 0.448, = 0.034) and ACP (OR = 0.262, = 0.045). Genetically predicted higher consumption of pork (OR = 5.618, = 0.022) or processed meat (OR = 2.771, = 0.007) had a significant causal association with AP, and genetically predicted higher processed meat intake increased the risk of CP (OR = 2.463, = 0.043). Our MR study showed that fruit intake may be protective against pancreatitis, whereas dietary intake of processed meat has potential adverse impacts. These findings may inform prevention strategies and interventions directed toward dietary habits and pancreatitis.
10.3390/nu15051153
Constipation and cardiovascular disease: A two-sample Mendelian randomization analysis.
Frontiers in cardiovascular medicine
Background:Although several observational studies have suggested positive associations between constipation and cardiovascular disease (CVD), a solid causal association has not been demonstrated. Therefore, a two-sample Mendelian randomization (MR) study was performed to investigate the causal associations between constipation and CVD. Methods:Independent genetic variants strongly associated with constipation were obtained from the FinnGen consortium. Summary-level data for CVD, including coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), stroke, and its subtypes, were collected from a few extensive genome-wide association studies (GWASs). The inverse-variance weighted methods, weighted median, and MR-Egger were used for the MR estimates. The Cochran's Q test, MR-Egger intercept tests, MR-PRESSO, MR Steiger test, leave-one-out analyses, and funnel plot were used in the sensitivity analysis. Results:Genetically determined constipation was suggestively associated with AF risk (odds ratio (OR), 1.07; 95% confidence interval (CI), 1.01, 1.14; = 0.016). Constipation and other CVD do not appear to be causally related. It was demonstrated that the results were robust through sensitivity analyses. Conclusion:This MR study demonstrated suggestive causal associations of constipation on AF, despite no associations achieving a significance value after multiple testing corrections. There was no evidence of an association between constipation and the risk of CAD, MI, HF, stroke, or stroke subtypes.
10.3389/fcvm.2023.1080982
Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses.
EBioMedicine
BACKGROUND:Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD. METHODS:Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants. FINDINGS:Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis. INTERPRETATION:The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD. FUNDING:SCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).
10.1016/j.ebiom.2023.104494
Association between Arachidonic Acid and the Risk of Schizophrenia: A Cross-National Study and Mendelian Randomization Analysis.
Nutrients
Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (r = -0.577, < 0.01; r = -0.626, < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia (OR = 0.986, OR = 0.148). In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.
10.3390/nu15051195
Roles of gut microbiome in epilepsy risk: A Mendelian randomization study.
Frontiers in microbiology
Background:Recent studies have suggested an association between gut microbiomes (GMs) and epilepsy. However, the GM taxa identified in different studies are variable. In addition, observational studies cannot indicate causality. Therefore, our study aimed to explore the causal association of GMs with epilepsy and identify the most influential GM taxa. Methods:We conducted a Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS) of 211 GM taxa and epilepsy. The GWAS summary statistics for 211 GM taxa (from phylum to genus level) were generated by the MiBioGen consortium, while the FinnGen consortium provided the GWAS summary statistics for epilepsy. The primary analytical method to assess causality was the inverse-variance weighted (IVW) approach. To complement the IVW method, we also applied four additional MR methods: MR-Egger, weighted median, simple mode, and weighted. In addition, we conducted sensitivity analyses using Cochrane's -test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results:We evaluated the causal effect of 211 GM taxa (from phylum to genus level) on epilepsy, generalized epilepsy, and focal epilepsy. After using the Bonferroni method for multiple testing correction, [odds ratio (OR) = 1.357, 95% confidence interval (CI): 1.126-1.635, = 0.001] and (OR = 1.336, 95% CI: 1.112-1.606, = 0.002). In addition, 21 nominally significant causal relationships were also identified. Further, the MR-Egger intercept test and MR-PRESSO global test suggested that our MR analysis was unaffected by horizontal pleiotropy ( > 0.05). Finally, the leave-one-out analysis suggested the robustness of the results. Conclusion:Through the MR study, we analyzed the causal relationship of 211 GM taxa with epilepsy and determined the specific intestinal flora associated with increased epilepsy risk. Our findings may provide helpful biomarkers for disease progression and potential candidate therapeutic targets for epilepsy. In addition, in-depth analysis of large-scale microbiome GWAS datasets based on metagenomics sequencing is necessary for future studies.
10.3389/fmicb.2023.1115014
Micronutrients and risks of three main urologic cancers: A mendelian randomization study.
Frontiers in nutrition
Background:The effect of micronutrients on urologic cancers has been explored in observational studies. We conducted the two-sample mendelian randomization (TSMR) study to investigate whether micronutrients could causally influence the risk of urologic cancers. Methods:Summary statistics for four micronutrients and three main urologic cancers outcomes were obtained from genome-wide association studies (GWAS). MR analyses were applied to explore the potential causal association between them. Sensitivity analyses using multiple methods were also conducted. Results:Genetically predicted one SD increase in serum copper and iron concentrations was causally associated with increased risks of renal cell carcinoma (RCC) (OR = 3.021, 95%CI = 2.204-4.687, < 0.001, male; OR = 2.231, 95%CI = 1.524-3.953, < 0.001, female; OR = 1.595, 95%CI = 1.310-1.758, = 0.0238, male; OR = 1.484, 95%CI = 1.197-2.337, = 0.0210, female, respectively) and per SD increase in serum zinc levels was related to decreased risks of RCC (OR = 0.131, 95%CI = 0.0159-0.208, < 0.001, male; OR = 0.124, 95%CI = 0.0434-0.356, < 0.001, female). No significant results were observed between micronutrients and the risk of bladder cancer after Bonferroni correction. Additionally, per SD increase in serum zinc level was associated with a 5.8% higher risk of prostate cancer (PCa) [OR = 1.058, 95%CI = 1.002-1.116, = 0.0403, inverse-variance weight (IVW)]. Conclusions:Micronutrients play a vital role in the development of urological tumors. Future studies are required to replicate the findings, explore the underlying mechanisms, and examine the preventive or therapeutic role of micronutrients in clinical settings.
10.3389/fnut.2023.1016243
Sex-Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.
Journal of the American Heart Association
Background Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. Methods and Results Uncorrelated (<0.001), genome-wide significant (<5×10) single-nucleotide polymorphisms were extracted from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse-variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28-1.74], =3.72×10) heart failure (OR, 1.27 [95% CI, 1.06-1.53], =0.009), and stroke (OR, 1.25 [95% CI, 1.00-1.56], =0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16-7.29], =0.023), heart failure (OR, 1.90 [95% CI, 1.28-2.82], =0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03-3.37], =0.039), and stroke (OR, 2.07 [95% CI, 1.22-3.52], =0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06-1.14], =1.68×10) and heart failure (OR, 1.12 [95% CI, 1.07-1.17], =5.06×10); both associations were at least partly mediated by body mass index. Conclusions These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.
10.1161/JAHA.122.027933
Causal association of the brain structure with the susceptibility, hospitalization, and severity of COVID-19: A large-scale genetic correlation study.
Journal of medical virology
Brain structure is related to its ability to resist external pathogens. Furthermore, there are several abnormal anatomical brain events and central system symptoms associated with COVID-19. This study, which was conducted based on genetic variables, aimed to identify the causal association between brain structure and COVID-19 phenotypes. We performed a two-sample bidirectional Mendelian randomization analysis using genetic variables obtained from large genome-wide association studies as instruments to identify the potential causal effects of various brain imaging-derived phenotypes (BIDPs) traits on susceptibility, hospitalisation, and severity of COVID-19. We explored the genetic correlations of 1325 BIDPs with the susceptibility, hospitalisation, and severity of COVID-19 using Linkage Disequilibrium Score Regression. We observed a causal relationship between increased cortical thickness of the left inferior temporal area and an increased risk of increased COVID-19 infection (p = 4.29 × 10-4) and hospitalisation (p = 3.67 × 10-3). Moreover, the larger total surface area of the whole brain was negatively correlated with the risk of hospitalisation for COVID-19. Furthermore, there was a significant causal association between increased cerebrospinal fluid volume and decreased severity of COVID-19 (p = 3.74 × 10-3). In a conclusion, we provide new insights into the causal association between BIDPs and COVID-19 phenotypes, which may help elucidate the aetiology of COVID-19.
10.1002/jmv.28651
Associations of serum uric acid levels with liver disease-related morbidity and mortality: A prospective cohort study of the UK Biobank.
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND AND AIMS:The association of serum uric acid (SUA) levels with liver-related morbidity and mortality remains undetermined. Therefore, we aimed to explore the association of SUA levels with liver-related morbidity and mortality. METHODS:The present cohort study included 459 619 adults from the UK Biobank. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of SUA levels with morbidity and mortality of overall liver disease. Mendelian randomization (MR) analyses were conducted to explore the underlying causality. A polygenic risk score was generated to assess whether there was a gene-exposure interaction. RESULTS:During a median follow-up of 12.6 years, 14 302 nonfatal and 609 fatal cases of overall liver disease were identified. Compared to individuals in the lowest quartile, the HRs (95% CI) of incident overall liver disease were 1.08 (1.02-1.14), 1.13 (1.07-1.20) and 1.44 (1.36-1.53) for individuals with SUA levels in quartiles 2, 3 and 4 respectively. Similarly, the HRs (95% CI) of liver disease-associated mortality were 1.09 (0.78-1.52), 1.55 (1.14-2.13) and 1.96 (1.42-2.69) for individuals with SUA levels in quartiles 2, 3 and 4 respectively. The MR results did not support the causal association of SUA levels with liver disease. In addition, there was a significant modification effect of the polygenic risk score on the association of SUA levels with incident overall liver disease (p = .003). CONCLUSIONS:Higher SUA levels were significantly associated with an increased risk of overall liver disease morbidity and mortality.
10.1111/liv.15564
The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study.
European journal of epidemiology
Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival.
10.1007/s10654-023-00979-5
Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder.
Molecular psychiatry
Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.
10.1038/s41380-022-01544-4
Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer.
JAMA oncology
Importance:The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited. Objective:To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer. Design, Setting, and Participants:This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022. Exposures:Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization. Main Outcomes and Measures:The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression. Results:Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival. Conclusions and Relevance:This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT01150045.
10.1001/jamaoncol.2022.6911
The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: a Mendelian randomization study.
Human molecular genetics
Despite early interest, the evidence linking fatty acids to cardiovascular diseases (CVDs) remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the etiology of several CVD endpoints in up to 1 153 768 European (maximum 123 668 cases) and 212 453 East Asian (maximum 29 319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple CVDs, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL) cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the etiology of CVDs and suggest LDL cholesterol as a potential mediating trait between PUFA biosynthesis and CVDs risk.
10.1093/hmg/ddac153
Effect of basal metabolic rate on osteoporosis: A Mendelian randomization study.
Frontiers in public health
Purpose:Basal metabolic rate may play a key role in the pathogenesis and progression of osteoporosis. We performed Mendelian random analysis to evaluate the causal relationship between basal metabolic rate and osteoporosis. Methods:Instrumental variables for the basal metabolic rate were selected. We used the inverse variance weighting approach as the main Mendelian random analysis method to estimate causal effects based on the summary-level data for osteoporosis from genome-wide association studies. Results:A potential causal association was observed between basal metabolic rate and risks of osteoporosis (odds ratio = 0.9923, 95% confidence interval: 0.9898-0.9949; = 4.005). The secondary MR also revealed that BMR was causally associated with osteoporosis (odds ratio = 0.9939, 95% confidence interval: 0.9911-0.9966; = 1.038). The accuracy and robustness of the findings were confirmed using sensitivity tests. Conclusion:Basal metabolic rate may play a causal role in the development of osteoporosis, although the underlying mechanisms require further investigation.
10.3389/fpubh.2023.1096519
Dietary factors and risk for asthma: A Mendelian randomization analysis.
Frontiers in immunology
Background:Previous research has found a link between dietary factors and asthma. However, few studies have analyzed the relationship between dietary factors and asthma using Mendelian randomization. Methods: The IEU Open GWAS project (https://gwas.mrcieu.ac.uk/) was the source of exposure and outcome datasets. The exposure datasets included Alcoholic drinks per week, Alcohol intake frequency, Processed meat intake, Poultry intake, Beef intake, Non-oily fish intake, Oily fish intake, Pork intake, Lamb/mutton intake, Bread intake, Cheese intake, Cooked vegetable intake, Tea intake, Fresh fruit intake, Cereal intake, Salad/raw vegetable intake, Coffee intake, and Dried fruit intake. The weighted median, MR-Egger, and Inverse Variance Weighted methods were used as the main methods of Mendelian randomization analysis. Heterogeneity and pleiotropic analysis were performed to ensure the accuracy of the results. Results:Alcohol intake frequency (after removing outliers OR: 1.217; 95% CI: 1.048-1.413; p=0.00993) was related to an increased risk of Asthma. Fresh fruit intake (OR: 0.489; 95% CI: 0.320-0.748; p=0.000954) and Dried fruit intake (after removing outliers OR: 0.482; 95% CI: 0.325-0.717; p= 0.000312) were discovered as protective factors. Other dietary intakes found no causal relationship with asthma. Conclusion:This study found that dried fruit intake and fresh fruit intake were associated with a reduced risk of asthma, and alcohol intake frequency was associated with an increased risk of asthma. This study also found that other factors included in this study were not associated with asthma.
10.3389/fimmu.2023.1126457
Assessment of the association between genetic factors regulating thyroid function and microvascular complications in diabetes: A two-sample Mendelian randomization study in the European population.
Frontiers in endocrinology
Background:Observational studies have identified a possible link between thyroid function and diabetic microangiopathy, specifically in diabetic kidney disease (DKD) and diabetic retinopathy (DR). However, it is unclear whether this association reflects a causal relationship. Objective:To assess the potential direct effect of thyroid characteristics on DKD and DR based on Mendelian randomization (MR). Methods:We conducted an MR study using genetic variants as an instrument associated with thyroid function to examine the causal effects on DKD and DR. The study included the analysis of 4 exposure factors associated with thyroid hormone regulation and 5 outcomes. Genomewide significant variants were used as instruments for standardized freethyroxine (FT4) and thyroid-stimulating hormone (TSH) levels within the reference range, standardized free triiodothyronine (FT3):FT4 ratio, and standardized thyroid peroxidase antibody (TPOAB) levels. The primary outcomes were DKD and DR events, and secondary outcomes were estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR) in diabetes, and proliferative diabetic retinopathy (PDR). Satisfying the 3 MR core assumptions, the inverse-variance weighted technique was used as the primary analysis, and sensitivity analysis was performed using MR-Egger, weighted median, and MR pleiotropy residual sum and outlier techniques. Results:All outcome and exposure instruments were selected from publicly available GWAS data conducted in European populations. In inverse-variance weighted random-effects MR, gene-based TSH with in the reference range was associated with DKD (OR 1.44; 95%CI 1.04, 2.41; P = 0.033) and eGFR (β: -0.031; 95%CI: -0.063, -0.001; P = 0.047). Gene-based increased FT3:FT4 ratio, decreased FT4 with in the reference range were associated with increased ACR with inverse-variance weighted random-effects β of 0.178 (95%CI: 0.004, 0.353; P = 0.046) and -0.078 (95%CI: -0.142, -0.014; P = 0.017), respectively, and robust to tests of horizontal pleiotropy. However, all thyroid hormone instruments were not associated with DR and PDR at the genetic level. Conclusion:In diabetic patients, an elevated TSH within the reference range was linked to a greater risk of DKD and decreased eGFR. Similarly, decreased FT4 and an increased FT3:FT4 ratio within the reference range were associated with increased ACR in diabetic patients. However, gene-based thyroid hormones were not associated with DR, indicating a possible pathway involving the thyroid-islet-renal axis. However, larger population studies are needed to further validate this conclusion.
10.3389/fendo.2023.1126339
Allometric body shape indices, type 2 diabetes and kidney function: A two-sample Mendelian randomization study.
Diabetes, obesity & metabolism
AIM:To examine the association between body mass index (BMI)-independent allometric body shape indices and kidney function. MATERIALS AND METHODS:We performed a two-sample Mendelian randomization (MR) analysis, using summary statistics from UK Biobank, CKDGen and DIAGRAM. BMI-independent allometric body shape indices were: A Body Shape Index (ABSI), Waist-Hip Index (WHI) and Hip Index (HI). Kidney function outcomes were: urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate and blood urea nitrogen. Furthermore, we investigated type 2 diabetes (T2D) as a potential mediator on the pathway to albuminuria. The main analysis was inverse variance-weighted random-effects MR in participants of European ancestry. We also performed several sensitivity MR analyses. RESULTS:A 1-standard deviation (SD) increase in genetically predicted ABSI and WHI levels was associated with higher UACR (β = 0.039 [95% confidence interval: 0.016, 0.063] log [UACR], P = 0.001 for ABSI, and β = 0.028 [0.012, 0.044] log [UACR], P = 6 x 10 for WHI) in women, but not in men. Meanwhile, a 1-SD increase in genetically predicted HI was associated with lower UACR in women (β = -0.021 [-0.041, 0.000] log [UACR], P = 0.05) and in men (β = -0.026 [-0.058, 0.005] log [UACR], P = 0.10). Corresponding estimates in individuals with diabetes were substantially augmented. Risk of T2D increased for genetically high ABSI and WHI in women (P < 6 x 10 ) only, but decreased for genetically high HI in both sexes (P < 9 x 10 ). No other associations were observed. CONCLUSIONS:Genetically high HI was associated with decreased risk of albuminuria, mediated through decreased T2D risk in both sexes. Opposite associations applied to genetically high ABSI and WHI in women only.
10.1111/dom.15037
Association of genetically predicted lipid traits and lipid-modifying targets with heart failure.
European journal of preventive cardiology
AIMS:To assess the association of genetically predicted lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF). METHODS AND RESULTS:Two-sample Mendelian randomization (MR) study was conducted using summary-level genome-wide association studies (GWASs) from UK Biobank and HERMES Consortium. Genetic variants obtained from UK Biobank GWAS data were selected as instrumental variables to predict the level of lipid traits [LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB), and apolipoprotein AI (ApoAI)] and lipid-modifying effect of eight drug targets [HMGCR, PCSK9, NPC1L1, PPARA, lipoprotein lipase (LPL), ANGPTL3, APOC3, and cholesteryl ester transfer protein (CETP)]. In this study, we observed that genetically predicted LDL-C, TG, HDL-C or ApoB were significantly related to HF, which were mainly mediated by coronary heart disease (CHD). Drug target MR analyses identified PCSK9, CETP, and LPL as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C = 1.27*10-4; PApoB = 1.94*10-4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P = 5.87*10-6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P = 3.73*10-12). CONCLUSION:This two-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition, and LPL activation were effective in HF reduction.
10.1093/eurjpc/zwac290
Childhood adiposity and novel subtypes of diabetes in adults: a Mendelian randomisation and genome-wide genetic correlation study.
The Lancet. Global health
BACKGROUND:Five novel subtypes of adult-onset diabetes were identified in 2018. We aimed to investigate whether childhood adiposity increases the risks of these subtypes using a Mendelian randomisation design, and to explore genetic overlaps between body size (self-reported perceived body size [ie, thinner, about average, or plumper] in childhood, and BMI measured in adulthood) and these subtypes. METHODS:The Mendelian randomisation and genetic correlation analyses were based on summary statistics from European genome-wide association studies of childhood body size (n=453 169), adult BMI (n=359 983), latent autoimmune diabetes in adults (n=8581), severe insulin-deficient diabetes (n=3937), severe insulin-resistant diabetes (n=3874), mild obesity-related diabetes (n=4118), and mild age-related diabetes (n=5605). We identified 267 independent genetic variants as instrumental variables for childhood body size in the Mendelian randomisation analysis of latent autoimmune diabetes in adults and 258 independent genetic variants as instrumental variables for other diabetes subtypes. The inverse variance-weighted method was used as the primary estimator in the Mendelian randomisation analysis, supplemented by other Mendelian randomisation estimators. We calculated overall genetic correlations (rg) between childhood or adult adiposity and different subtypes using linkage disequilibrium score regression. FINDINGS:A large childhood body size was associated with increased risk of latent autoimmune diabetes in adults (odds ratio [OR] 1·62, 95% CI 1·95-2·52), severe insulin-deficient diabetes (OR 2·45, 1·35-4·46), severe insulin-resistant diabetes (OR 3·08, 1·73-5·50), and mild obesity-related diabetes (OR 7·70, 4·32-13·7), but not mild age-related diabetes in the main Mendelian randomisation analysis. Other Mendelian randomisation estimators gave similar results and did not support the existence of horizontal pleiotropy. There was genetic overlap between childhood body size and mild obesity-related diabetes (rg 0·282; p=0·0003), and between adult BMI and all diabetes subtypes. INTERPRETATION:This study provides genetic evidence that higher childhood adiposity is a risk factor for all subtypes of adult-onset diabetes, except mild age-related diabetes. It is therefore important to prevent and intervene in childhood overweight or obesity. There is shared genetic contribution to childhood obesity and mild obesity-related diabetes. FUNDING:The study was supported by the China Scholarship Council, the Swedish Research Council (grant number 2018-03035), Research Council for Health, Working Life and Welfare (grant number 2018-00337), and Novo Nordisk Foundation (grant number NNF19OC0057274).
10.1016/S2214-109X(23)00086-4
Association of Lipid-Lowering Drugs With Risk of Psoriasis: A Mendelian Randomization Study.
JAMA dermatology
Importance:Lipid pathways have been implicated in the pathogenesis of psoriasis, and some lipid-lowering drugs, such as statins, are hypothesized to have disease-modifying properties. However, large population-level studies are scarce, and causal interpretation of results from traditional observational designs is limited by confounding. Objective:To investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk. Design, Setting, and Participants:This 2-sample mendelian randomization study was performed from August to October 2022 and included population-level genome-wide association studies of psoriasis in the UK Biobank and FinnGen studies and low-density lipoprotein (LDL) by the Global Lipids Genetics Consortium. The inverse variance-weighted method was used with pleiotropy robust methods and colocalization as sensitivity analyses. Exposures:Genetically proxied inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR, targeted by statins), Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by, eg, alirocumab), using LDL as the biomarker. Main Outcomes and Measures:Risk of psoriasis. Results:Data from 12 116 patients with psoriasis and approximately 1.3 million individuals with LDL measurement were analyzed. Genetically proxied PCSK9 inhibition was associated with reduced risk of psoriasis (odds ratio, 0.69 per standard deviation reduction in LDL; 95% CI, 0.55-0.88; P = .003), which was replicated in FinnGen (odds ratio, 0.71; 95% CI, 0.57-0.88; P = .002). Sensitivity analyses did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for HMGCR or NPC1L1 inhibition. Conclusions and Relevance:This mendelian randomization study suggests that PCSK9 is implicated in psoriasis pathogenesis, and its inhibition is associated with reduced psoriasis risk. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of psoriasis.
10.1001/jamadermatol.2022.6051
Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis.
Brain : a journal of neurology
Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple sclerosis have been developed and widely used. However, existing medications for multiple sclerosis were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for multiple sclerosis prevention are still needed. We performed Mendelian randomization to explore potential drug targets for multiple sclerosis using summary statistics from the International Multiple Sclerosis Genetics Consortium (nCase = 47 429, nControl = 68 374) and further replicated in UK Biobank (nCase = 1356, nControl = 395 209) and FinnGen cohorts (nCase = 1326, nControl = 359 815). Genetic instruments for 734 plasma and 154 CSF proteins were obtained from recently published genome-wide association studies. The reverse causality detection using bidirectional Mendelian randomization analysis and Steiger filtering, Bayesian co-localization, and phenotype scanning that searched previously reported genetic variant-trait associations were implemented to consolidate the Mendelian randomization findings further. In addition, the protein-protein interaction network was performed to reveal potential associations among proteins and/or present multiple sclerosis medications. At Bonferroni significance (P < 5.63 × 10-5), Mendelian randomization analysis revealed six protein-multiple sclerosis pairs. In plasma, per standard deviation increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratios for the proteins above were 0.83 (95% CI, 0.79-0.89), 0.59 (95% CI, 0.48-0.71) and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of multiple sclerosis, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six proteins had reverse causality. Bayesian co-localization suggested that FCRL3 [coloc.abf-posterior probability of hypothesis 4 (PPH4) = 0.889], TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930) and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with multiple sclerosis. FCRL3, TYMP and SLAMF7 interacted with target proteins of current multiple sclerosis medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1 and SLAMF7 had causal effects on multiple sclerosis risk. These findings suggested those five proteins might be promising drug targets for multiple sclerosis and warrant further clinical investigation, especially FCRL3 and SLAMF7.
10.1093/brain/awad070
Serum Urate and Risk of Chronic Kidney Disease: A Mendelian Randomization Study Using Taiwan Biobank.
Mayo Clinic proceedings
OBJECTIVE:To evaluate the association between serum urate and risk of incident chronic kidney disease (CKD) and to assess whether serum urate plays a causal role in CKD. PATIENTS AND METHODS:We conducted a prospective cohort study and Mendelian randomization analysis that analyzed longitudinal data from the Taiwan Biobank between January 1, 2012, and December 31, 2021. RESULTS:A total of 34,831 individuals met the inclusion criteria, of which 4697 (13.5%) had hyperuricemia. After a median (interquartile range) follow-up of 4.1 (3.1-4.9) years, 429 participants developed CKD. After adjustment for age, sex, and comorbid conditions, each mg/dL increase in serum urate was associated with a 15% higher risk of incident CKD (HR, 1.15; 95% CI, 1.08 to 1.24; P<.001). The genetic risk score and seven Mendelian randomization methods revealed no significant association between serum urate levels and the risk of incident CKD (HR, 1.03; 95% CI, 0.72 to 1.46; P=0.89; all P>.05 for 7 Mendelian randomization methods). CONCLUSION:This prospective, population-based cohort study showed that elevated serum urate is a significant risk factor for incident CKD; however, Mendelian randomization analyses failed to provide evidence that serum urate had a causal effect on CKD in the East Asian population.
10.1016/j.mayocp.2023.01.004
Circulating insulin-like growth factor-1 and risk of lung diseases: A Mendelian randomization analysis.
Frontiers in endocrinology
Background:Insulin-like growth factor-1 (IGF-1) display a vital role in in the pathogenesis of lung diseases, however, the relationship between circulating IGF-1 and lung disease remains unclear. Methods:Single nucleotide polymorphisms (SNPs) associated with the serum levels of IGF-1 and the outcomes data of lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer and idiopathic pulmonary fibrosis (IPF) were screened from the public genome-wide association studies (GWAS). Two-sample Mendelian randomization (MR) analysis was then performed to assess the independent impact of IGF-1 exposure on these lung diseases. Results:Totally, 416 SNPs related to circulating IGF-1 levels among 358,072 participants in UK Biobank. According to a primary casual effects model with MR analyses by the inverse variance weighted (IVW) method, the circulating IGF-1 was demonstrated a significantly related with the risk of asthma (OR, 0.992; 95% CI, 0.985-0.999, =0.0324), while circulating IGF-1 showed no significant correlation with CODP (OR, 1.000; 95% CI, 0.999-1.001, =0.758), lung cancer (OR, 0.979, 95% CI, 0.849-1.129, =0.773), as well as IPIGFF (OR, 1.100, 95% CI, 0.794-1.525, =0.568). Conclusion:The present study demonstrated that circulating IGF-1 may be causally related to lower risk of asthma.
10.3389/fendo.2023.1126397
Association between brain structures and migraine: A bidirectional Mendelian randomization study.
Frontiers in neuroscience
Background:Accumulating evidence of clinical and neuroimaging studies indicated that migraine is related to brain structural alterations. However, it is still not clear whether the associations of brain structural alterations with migraine are likely to be causal, or could be explained by reverse causality confounding. Methods:We carried on a bidirectional Mendelian randomization analysis in order to identify the causal relationship between brain structures and migraine risk. Summary-level data and independent variants used as instruments came from large genome-wide association studies of total surface area and average thickness of cortex (33,992 participants), gray matter volume (8,428 participants), white matter hyperintensities (50,970 participants), hippocampal volume (33,536 participants), and migraine (102,084 cases and 771,257 controls). Results:We identified suggestive associations of the decreased surface area (OR = 0.85; 95% CI, 0.75-0.96; = 0.007), and decreased hippocampal volume (OR = 0.74; 95% CI, 0.55-1.00; = 0.047) with higher migraine risk. We did not find any significant association of gray matter volume, cortical thickness, or white matter hyperintensities with migraine. No evidence supporting the significant association was found in the reverse MR analysis. Conclusion:We provided suggestive evidence that surface area and hippocampal volume are causally associated with migraine risk.
10.3389/fnins.2023.1148458
Impaired pulmonary function mediates the impact of preterm birth on later-life stroke: a 2-step, multivariable Mendelian randomization study.
Epidemiology and health
OBJECTIVES:Observational studies have suggested an association between preterm birth and stroke in late adulthood, but it remains unclear whether the association is causal. The purpose of this study was to evaluate the causal effects of gestational age on stroke and to determine the pathophysiological mechanisms underlying the causal associations. METHODS:Two-sample Mendelian randomization (MR) was performed to assess the causal effects of fetal gestational duration, early preterm birth (EPB), preterm birth, or postterm birth on stroke and its subtypes. Two-step Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were additionally used to determine the role of common stroke risk factors, including cardiovascular diseases, hypertension, pulmonary impairment, inflammation, and metabolic diseases, in mediating the causal associations between gestational age and stroke and its subtypes. RESULTS:Genetically predicted EPB increased the risk of cardioembolic stroke (CES; odds ratio [OR], 1.115; 95% confidence interval [CI], 1.036 to 1.200; p=0.004) and large artery stroke (LAS; OR, 1.131; 95% CI, 1.031 to 1.241; p=0.009). The TSMR results showed that EPB was associated with a lower forced expiratory volume in the first second and forced vital capacity ratio (FEV1/FVC) (β=-0.020; 95% CI, -0.035 to -0.005; p=0.009), which increased the risk of CES and LAS. Further MVMR analysis showed that the associations between EPB and stroke disappeared after adjustment for FEV1/FVC. CONCLUSIONS:Our data demonstrate that EPB is causally associated with an elevated risk of CES and LAS, and that pulmonary dysfunction mediates the causal impact of EPB on CES and LAS.
10.4178/epih.e2023031
Bi-directional causal effect between vitamin B12 and non-alcoholic fatty liver disease: Inferring from large population data.
Frontiers in nutrition
Objectives:Many observational studies evaluate the association between vitamin B12 and non-alcoholic fatty liver disease (NAFLD). However, the causality of this association remains uncertain, especially in European populations. We conducted a bidirectional Mendelian randomization study to explore the association between vitamin B12 and NAFLD. Methods:Two-sample Mendelian randomization study was conducted. Summary statistics for vitamin B12 were acquired from a genome-wide association studies (GWAS) meta-analysis including 45,576 subjects. Summary-level data for NAFLD was obtained from a GWAS meta-analysis of 8,434 cases and 770,180 non-cases and another GWAS meta-analysis of 1,483 cases and 17,781 non-cases. Summary-level data for 4 enzymes including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT), was available from the UK Biobank. Inverse variance weighting (as main analysis), weighted median estimate, robust adjusted profile score, MR-Egger, and MR-PRESSO (sensitivity analyses) were performed to calculate causal estimates. Results:Genetically predicted higher vitamin B12 concentrations were consistently associated with an increased NAFLD in two sources. The combined odds ratio (OR) of NAFLD was 1.30 (95% confidence interval (CI), 1.13 to 1.48; < 0.001) per SD-increase in vitamin B12 concentrations. Genetic liability to NAFLD was also positively associated with vitamin B12 concentrations (Beta 0.08, 95%CI, 0.01 to 0.16; = 0.034). Sensitivity analyses also revealed consistent results. Genetically predicted vitamin B12 concentrations showed no significant association with liver enzymes. Conclusion:The present study indicates that increased serum vitamin B12 concentrations may play a role in NAFLD risk. NAFLD also has a causal impact on elevated vitamin B12 concentrations in the circulation. Notably, vitamin B12 concentrations imply the levels of vitamin B12 in the circulation, and higher intake of vitamin B12 may not directly lead to higher levels of serum vitamin B12, instead the higher levels of vitamin B12 in the circulation may be caused by the dysregulation of the metabolism of this vitamin in this study. There exist bidirectional causal effects between serum vitamin B12 concentrations and risk of NAFLD in European individuals.
10.3389/fnut.2023.1015046
A sex- and site-specific relationship between body mass index and osteoarthritis: evidence from observational and genetic analyses.
Osteoarthritis and cartilage
OBJECTIVE:We primarily aimed to investigate whether there are phenotypic and genetic links underlying body mass index (BMI) and overall osteoarthritis (OA). We then intended to explore whether the relationships differ across sexes and sites. METHOD:We first evaluated the phenotypic association between BMI and overall OA using data from the UK Biobank. We then investigated the genetic relationship leveraging summary statistics of the hitherto largest genome-wide association studies performed for BMI and overall OA. Finally, we repeated all analyses in a sex- (female, male) and site- (knee, hip, spine) specific manner. RESULTS:Observational analysis suggested an increased hazard of diagnosed OA per 5 kg/m increment in BMI (hazard ratio = 1.38, 95% confidence interval (CI) = 1.37-1.39). A positive overall genetic correlation was observed for BMI and OA (r = 0.43, P = 4.72 × 10), corroborated by 11 significant local signals. Cross-trait meta-analysis identified 34 pleiotropic loci shared between BMI and OA, of which seven were novel. Transcriptome-wide association study revealed 29 shared gene-tissue pairs, targeting nervous, digestive, and exo/endocrine systems. Mendelian randomization demonstrated a robust BMI-OA causal relationship (odds ratio = 1.47, 95% CI = 1.42-1.52). A similar pattern of effects was observed in sex- and site-specific analyses, with BMI affecting OA comparably in both sexes and most strongly in the knee. CONCLUSION:Our work demonstrates an intrinsic relationship underlying BMI and overall OA, reflected by a pronounced phenotypic association, significant biological pleiotropy, and a putative causal link. Stratified analysis further reveals that the effects are distinct across sites and comparable across sexes.
10.1016/j.joca.2023.02.073
Causal effects for genetic variants of osteoprotegerin on the risk of acute myocardial infarction and coronary heart disease: A two-sample Mendelian randomization study.
Frontiers in cardiovascular medicine
Although since the 1980s, the mortality of coronary heart disease(CHD) has obviously decreased due to the rise of coronary intervention, the mortality and disability of CHD were still high in some countries. Etiological studies of acute myocardial infarction(AMI) and CHD were extremely important. In this study, we used two-sample Mendelian randomization(TSMR) method to collect GWAS statistics of osteoprotegerin (OPG), AMI and CHD to reveal the causal relationship between OPG and these two diseases. In total, we identified 7 genetic variants associated with AMI and 7 genetic variants associated with CHD that were not found to be in linkage disequilibrium(LD; < 0.001). Evidence of a positive effect of an OPG genetic susceptibility on AMI was discovered(IVW OR = 0.877; 95% CI = 0.787-0.977; = 0.017; 7 SNPs) and CHD (IVW OR = 0.892; 95% CI = 0.803-0.991; = 0.033; 7 SNPs). After removing the influence of rs1385492, we found that there was a correlation between OPG and AMI/CHD (AMI: weighted median OR = 0.818;95% CI = 0.724-0.950; = 0.001; 6SNPs;CHD: weighted median OR = 0.842; 95% CI = 0.755-0.938; = 1.893 × 10; 6SNPs). The findings of our study indicated that OPG had a tight genetic causation association with MI or CHD. This genetic causal relationship presented us with fresh ideas for the etiology of AMI and CHD, which is an area of research that will continue in the future.
10.3389/fcvm.2023.1041231
Circulating levels of micronutrients and risk of infections: a Mendelian randomization study.
BMC medicine
BACKGROUND:Micronutrients play an essential role at every stage of the immune response, and deficiencies can therefore lead to increased susceptibility to infections. Previous observational studies and randomized controlled trials of micronutrients and infections are limited. We performed Mendelian randomization (MR) analyses to evaluate the effect of blood levels of eight micronutrients (copper, iron, selenium, zinc, beta-carotene, vitamin B12, vitamin C, and vitamin D) on the risk of three infections (gastrointestinal infections, pneumonia, and urinary tract infections). METHODS:Two-sample MR was conducted using publicly available summary statistics from independent cohorts of European ancestry. For the three infections, we used data from UK Biobank and FinnGen. Inverse variance-weighted MR analyses were performed, together with a range of sensitivity analyses. The threshold for statistical significance was set at P < 2.08E-03. RESULTS:We found a significant association between circulating levels of copper and risk of gastrointestinal infections, where a one standard deviation increase in blood levels of copper was associated with an odds ratio of gastrointestinal infections of 0.91 (95% confidence interval 0.87 to 0.97, P = 1.38E-03). This finding was robust in extensive sensitivity analyses. There was no clear association between the other micronutrients and the risk of infection. CONCLUSIONS:Our results strongly support a role of copper in the susceptibility to gastrointestinal infections.
10.1186/s12916-023-02780-3
Dyslipidemia and Risk of Preeclampsia: A Multiancestry Mendelian Randomization Study.
Hypertension (Dallas, Tex. : 1979)
BACKGROUND:Preeclampsia is a leading cause of maternal morbidity, and dyslipidemia has been associated with preeclampsia in observational studies. We use Mendelian randomization analyses to estimate the association between lipid levels, their pharmacological targets, and the risk of preeclampsia in 4 ancestry groups. METHODS:We extracted uncorrelated (<0.001) single-nucleotide polymorphisms strongly associated (<5×10) with LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and triglycerides from genome-wide association studies of European, admixed African, Latino, and East Asian ancestry participants. Genetic associations with risk of preeclampsia were extracted from studies of the same ancestry groups. Inverse-variance weighted analyses were performed separately for each ancestry group before they were meta-analyzed. Sensitivity analyses were conducted to evaluate bias due to genetic pleiotropy, demography, and indirect genetic effects. RESULTS:The meta-analysis across 4 ancestry groups included 1.5 million subjects with lipid measurements, 7425 subjects with preeclampsia, and 239 290 without preeclampsia. Increasing HDL-C was associated with reduced risk of preeclampsia (odds ratio, 0.84 [95% CI, 0.74-0.94]; =0.004; per SD increase in HDL-C), which was consistent across sensitivity analyses. We also observed cholesteryl ester transfer protein inhibition-a drug target that increases HDL-C-may have a protective effect. We observed no consistent effect of LDL-C or triglycerides on the risk of preeclampsia. CONCLUSIONS:We observed a protective effect of elevated HDL-C on risk of preeclampsia. Our findings align with the lack of effect in trials of LDL-C modifying drugs but suggest that HDL-C may be a new target for screening and intervention.
10.1161/HYPERTENSIONAHA.122.20426
A bi-directional Mendelian randomization study of sarcopenia-related traits and type 2 diabetes mellitus.
Frontiers in endocrinology
Background:Previous studies have reported an association between sarcopenia and type 2 diabetes mellitus (T2DM), but causation was prone to confounding factors. A more robust research approach is urgently required to investigate the causal relationship between sarcopenia and T2DM. Methods:The bi-directional two-sample MR study was carried out in two stages: Sarcopenia-related traits were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for hand-grip strength (n = 256,523), appendicular lean mass (ALM, n = 450,243), and walking pace (n = 459,915) were obtained from the UK Biobank. T2DM data were obtained from one of the biggest case-control studies on diabetes (DIAGRAM; n = 180,834 cases and 492,191 controls), which was published in 2022. The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed. Results:Low hand-grip strength had a potential causal relationship with an increased incidence of T2DM (OR = 1.109; 95% CI, 1.008-1.222; = 0.0350). T2DM risk was reduced by increasing ALM and walking pace: A 1 kg/m increase in ALM decreased the risk of T2DM by 10.2% (OR = 0.898; 95% CI, 0.830-0.952; < 0.001). A 1 m/s increase in walking pace decreased the risk of T2DM by 90.0% (OR = 0.100; 95% CI, 0.053-0.186; < 0.001). The relationship was bidirectional, with T2DM as a causative factor of sarcopenia-related traits ( < 0.05) except for ALM (β = 0.018; 95% CI, -0.008 to -0.044; = 0.168). Conclusions:Hand-grip strength and T2DM had a potential bidirectional causal relationship, as did walking pace and T2DM. We suggest that sarcopenia and T2DM may mutually have a significant causal effect on each other.
10.3389/fendo.2023.1109800
Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study.
Sleep
STUDY OBJECTIVES:Obstructive sleep apnea (OSA) had been associated with various cardiovascular diseases (CVDs) in observational studies, but causal inferences have not been confirmed. We used the Mendelian randomization (MR) study to explore the potential causal association between OSA with CVDs in the general population. METHODS:We performed a two-sample MR analysis using five gene-wide significant single-nucleotide polymorphisms associated with OSA at genome-wide significance from the FinnGen study (N = 217 955) and 12 cardiovascular diseases from the UK Biobank and the genetic consortia. The inverse-variance weight was chosen as the primary analysis and was complemented by various sensitivity analyses. The study design applied univariable MR, multivariable MR, and mediation analysis. RESULTS:MR analyses provide evidence of genetically predicted OSA on the risk of heart failure (odds ratio [OR],1.26; 95% confidence interval [CI],1.08 to 1.47), hypertension (OR,1.24; 95%CI, 1.11 to 1.39) and atrial fibrillation (OR,1.21; 95%CI,1.12 to 1.31). Multivariable MR indicated the adverse effect of OSA on heart failure persisted after adjusting BMI, smoking, drinking, and education (IVW OR,1.13; 95%CI, 1.01 to 1.27). However, the significance of hypertension and atrial fibrillation was dampened. Mediation analyses suggest that the causal association between OSA and heart failure is mediated in part by Apolipoprotein B, with a mediated portion of 9%. CONCLUSIONS:This study suggested that genetically predicted OSA is a potential causal risk factor for heart failure based on a large-scale population. Nevertheless, further studies regarding ancestral diversity are needed to confirm the causal association between OSA and CVDs.
10.1093/sleep/zsac298
Polycystic ovary syndrome and 25-hydroxyvitamin D: A bidirectional two-sample Mendelian randomization study.
Frontiers in endocrinology
Background:Accumulating observational studies have indicated that vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) < 50 nmol/L) is common in women with polycystic ovary syndrome (PCOS). However, the direction and causal nature remain unclear. In this study, we aimed to investigate the causal association between PCOS and 25OHD. Methods:A bidirectional two-sample Mendelian randomization (MR) study was used to evaluate the causal association between PCOS and 25OHD. From the publicly available European-lineage genome-wide association studies (GWAS) summary statistics for PCOS (4,890 cases of PCOS and 20,405 controls) and 25OHD (n = 417,580), we selected 11 and 102 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), respectively. In univariate MR (uvMR) analysis, inverse-variance weighted (IVW) method was employed in the primary MR analysis and multiple sensitivity analyses were implemented. Additionally, a multivariable MR (mvMR) design was carried to adjust for obesity and insulin resistance (IR) as well. Results:UvMR demonstrated that genetically determined PCOS was negatively associated with 25OHD level (IVW Beta: -0.02, = 0.008). However, mvMR found the causal effect disappeared when adjusting the influence of obesity and IR. Both uvMR and mvMR analysis didn't support the causal effect of 25OHD deficiency on risk of PCOS (IVW : 0.86, 95% : 0.66 ~ 1.12, = 0.280). Conclusion:Our findings highlighted that the casual effect of PCOS on 25OHD deficiency might be mediated by obesity and IR, and failed to find substantial causal effect of 25OHD deficiency on risk of PCOS. Further observational studies and clinical trials are necessary.
10.3389/fendo.2023.1110341
Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A bidirectional Mendelian randomization study.
Frontiers in immunology
Background:Multiple clinical studies have indicated that the gut microbiota influences the effects of immune checkpoint blockade (ICB) therapy comprising PD-1/PD-L1 inhibitors, but the causal relationship is unclear. Because of numerous confounders, many microbes related to PD-1/PD-L1 have not been identified. This study aimed to determine the causal relationship between the microbiota and PD-1/PD-L1 and identify possible biomarkers for ICB therapy. Method:We used bidirectional two-sample Mendelian randomization with two different thresholds to explore the potential causal relationship between the microbiota and PD-1/PD-L1 and species-level microbiota GWAS to verify the result. Result:In the primary forward analysis, genus_Holdemanella showed a negative correlation with PD-1 [βIVW = -0.25; 95% CI (-0.43 to -0.07); P = 0.028] and genus_Prevotella9 showed a positive correlation with PD-1 [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.027]; order_Rhodospirillales [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.044], family_Rhodospirillaceae [βIVW = 0.2; 95% CI (0 to 0.4); P = 0.032], genus_Ruminococcaceae_UCG005 [βIVW = 0.29; 95% CI (0.08 to 0.5); P = 0.028], genus_Ruminococcus_gnavus_group [βIVW = 0.22; 95% CI (0.05 to 0.4); P = 0.029], and genus_Coprococcus_2 [βIVW = 0.4; 95% CI (0.1 to 0.6); P = 0.018] were positively correlated with PD-L1; and phylum_Firmicutes [βIVW = -0.3; 95% CI (-0.4 to -0.1); P = 0.031], family_ClostridialesvadinBB60group [βIVW = -0.31; 95% CI (-0.5 to -0.11), P = 0.008], family_Ruminococcaceae [βIVW = -0.33; 95% CI (-0.58 to -0.07); P = 0.049], and genus_Ruminococcaceae_UCG014 [βIVW = -0.35; 95% CI (-0.57 to -0.13); P = 0.006] were negatively correlated with PD-L1. The one significant species in further analysis was species_Parabacteroides_unclassified [βIVW = 0.2; 95% CI (0-0.4); P = 0.029]. Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analyses confirmed the robustness of the MR results.
10.3389/fimmu.2023.1136169
The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis.
Frontiers in immunology
Background:Growing evidence shows a significant association between intestinal flora and allergic diseases, specifically atopic dermatitis (AD), allergic rhinitis (AR), and allergic asthma (AA). However, the causality has not yet been clarified. Objective:We conducted a bidirectional two-sample Mendelian randomization (TSMR) analysis to study the causal relationships between intestinal flora classification and AD, AR, or AA. Materials and methods:We obtained summary data of intestinal flora, AD, AR, and AA from a genome-wide association research. The inverse-variance weighted method is the primary method for analyzing causality in the TSMR analysis. Several sensitivity analyses were conducted to examine the stability of TSMR results. Reverse TSMR analysis was also performed to assess whether there was a reverse causality. Results:A total of 7 bacterial taxa associated with AD, AR, and AA were identified by the current TSMR analysis. Specifically, the genus Dialister(=0.034)and genus Prevotella(=0.047)were associated with a higher risk of AD, whereas class Coriobacteriia (=0.034) and its child taxon, order Coriobacteriales (=0.034) and family Coriobacteriaceae (=0.034), all had a protective effect on AR. In addition, the family Victivallaceae (=0.019) was identified as a risk factor for AR. We also noticed a positive association between the genus Holdemanella (=0.046) and AA. The reverse TSMR analysis didn't suggest any evidence of reverse causality from allergic diseases to the intestinal flora. Conclusion:We confirmed the causal relationship between intestinal flora and allergic diseases and provided an innovative perspective for research on allergic diseases: targeted regulation of dysregulation of specific bacterial taxa to prevent and treat AD, AR, and AA.
10.3389/fimmu.2023.1121273
Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus.
Journal of medical virology
Systemic lupus erythematosus (SLE) characterized by immune dysfunction is possibly more vulnerable to herpes simplex virus (HSV) infection. The infection has been intensively considered a common onset and exacerbation of SLE. This study is aimed at elucidating the causal association between SLE and HSV. A bidirectional two-sample Mendelian Randomization (TSMR) analysis was systematically conducted to explore the causal effect of SLE and HSV on each other. The causality was estimated by inverse variance weighted (IVW), MR-Egger and weighted median methods based on the summary-level genome-wide association studies (GWAS) data from a publicly available database. Genetically proxied HSV infection exhibited no causal association with SLE in the forward MR analysis using IVW method (odds ratio [OR] = 0.987; 95% confidence interval [CI]: 0.891-1.093; p = 0.798), nor did HSV-1 IgG (OR = 1.241; 95% CI: 0.874-1.762; p = 0.227) and HSV-2 IgG (OR = 0.934; 95% CI: 0.821-1.062; p = 0.297). Similar null results with HSV infection (OR = 1.021; 95% CI: 0.986-1.057; p = 0.245), HSV-1 IgG (OR = 1.003; 95% CI: 0.982-1.024; p = 0.788) and HSV-2 IgG (OR = 1.034; 95% CI: 0.991-1.080; p = 0.121) were observed in the reverse MR where SLE served as the exposure. Our study demonstrated no causal association between the genetically predicted HSV and SLE.
10.1002/jmv.28649
Association Between Systemic Lupus Erythematosus and Primary Hypothyroidism: Evidence from Complementary Genetic Methods.
The Journal of clinical endocrinology and metabolism
INTRODUCTION:Systemic lupus erythematosus (SLE) and hypothyroidism often coexist in observational studies; however, the causal relationship between them remains controversial. METHODS:Complementary genetic approaches, including genetic correlation, Mendelian randomization (MR), and colocalization analysis, were conducted to assess the potential causal association between SLE and primary hypothyroidism using summary statistics from large-scale genome-wide association studies. The association between SLE and thyroid-stimulating hormone (TSH) was further analyzed to help interpret the findings. In addition, findings were verified using a validation data set, as well as through different MR methods with different model assumptions. RESULTS:The linkage disequilibrium score regression revealed a shared genetic structure between SLE and primary hypothyroidism, with the significant genetic correlation estimated to be 0.2488 (P = 6.00 × 10-4). MR analysis with the inverse variance weighted method demonstrated a bidirectional causal relationship between SLE and primary hypothyroidism. The odds ratio (OR) of SLE on primary hypothyroidism was 1.037 (95% CI, 1.013-1.061; P = 2.00 × 10-3) and that of primary hypothyroidism on SLE was 1.359 (95% CI, 1.217-1.520; P < 0.001). The OR of SLE on TSH was 1.007 (95% CI, 1.001-1.013; P = 0.032). However, TSH was not causally associated with SLE (P = 0.152). Similar results were found using different MR methods. In addition, colocalization analysis suggested that shared causal variants existed between SLE and primary hypothyroidism. The results of the validation analysis indicated a bidirectional causal relationship between SLE and primary hypothyroidism, as well as shared loci. CONCLUSION:In summary, a bidirectional causal relationship between SLE and primary hypothyroidism was observed with complementary genetic approaches.
10.1210/clinem/dgac614
Genetically predicted levels of folate, vitamin B, and risk of autoimmune diseases: A Mendelian randomization study.
Frontiers in immunology
Background:Evidence from observational studies on the association of folate and vitamin B with autoimmune diseases are conflicting. Objective:We aimed to investigate the relationship of folate and vitamin B with autoimmune diseases using Mendelian randomization (MR). Materials and methods:We selected single-nucleotide polymorphisms associated with folate and vitamin B at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness. Results:We found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32-0.69; = 1.33 × 10]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression ( = 0.919). In addition, we observed that vitamin B per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03-1.26, = 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01-1.29, = 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01-1.28, =0.037), while the association was not significant after Bonferroni correction. Conclusion:The study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B and risk of IBD.
10.3389/fimmu.2023.1139799
The association between COVID-19 and cognitive performance: A Mendelian randomization analysis.
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:People with COVID-19 had poorer general cognitive functioning compared to people without COVID-19. The causal link between COVID-19 and cognitive impairment is still unknown. METHODS:Mendelian randomization (MR) is a statistical approach based on genome-wide association studies (GWAS) to construct instrumental variables (IVs) and can effectively bring down the confounding bias of environmental or other disease factors, because alleles are randomly assigned to offspring. RESULTS:There was consistent evidence that cognitive performance was causally associated with COVID-19; this suggests that people with better cognitive performance are less likely to be infected with COVID-19. The reverse MR analysis treating COVID-19 as the exposure and cognitive performance as the outcome demonstrated an insignificant association, indicating the unidirectionality of the relationship. DISCUSSION:Our study provided credible evidence that cognitive performance has an impact on COVID-19. Future research should focus on long-term impact of cognitive performance on COVID-19.
10.1002/alz.13017
Polyunsaturated fatty acids and risk of anorexia nervosa: A Mendelian randomization study.
Journal of affective disorders
PURPOSE:Observational studies have suggested that polyunsaturated fatty acids (PUFAs) decrease the risk of anorexia nervosa (AN). In the present study, we examined this hypothesis using a Mendelian randomization analysis. METHODS:We used summary statistics for single-nucleotide polymorphisms associated with plasma levels of n-6 (linoleic acid and arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) and the corresponding data for AN from a genome-wide association meta-analysis of 72,517 individuals (16,992 diagnosed AN cases and 55,525 controls). RESULTS:None of the genetically predicted PUFAs were significantly associated with the risk of AN; odds ratios (95 % confidence interval) per 1 standard deviation increase in PUFA levels were 1.03 (0.98, 1.08) for linoleic acid, 0.99 (0.96, 1.03) for arachidonic acid, 1.03 (0.94, 1.12) for alpha-linolenic acid, 0.98 (0.90, 1.08) for eicosapentaenoic acid, 0.96 (0.91, 1.02) for docosapentaenoic acid, and 1.01 (0.90, 1.36) for docosahexaenoic acid. LIMITATION:Only two types of fatty acids (LA and DPA) can be used for pleiotropy tests using the MR-Egger intercept test. CONCLUSION:This study does not support the hypothesis that PUFAs decrease the risk of AN.
10.1016/j.jad.2023.03.016
Delayed bedtime on non-school days associates with higher weight and waist circumference in children: Cross-sectional and longitudinal analyses with Mendelian randomisation.
Journal of sleep research
Sleep duration has been linked with obesity in population-based studies. Less is known about bedtimes and, especially, if discrepancy between bedtimes on school and non-school days associate with adiposity in children. The associations of self-reported bedtimes with the body mass index z-score (BMIz) and waist-to-height ratio (WtHr) were examined among children with a mean (SD) age of 11.2 (0.85) years in cross-sectional (n = 10,245) and longitudinal (n = 5085) study settings. The causal relationship of whether BMIz contributes to bedtimes, was further examined in a subset of 1064 participants by exploiting Mendelian randomisation (MR). After adjusting for sleep duration and other confounders, every 0.5 h later bedtime on non-school nights and a delay in bedtime in non-school nights compared with school nights associated with 0.048 (95% CI 0.027; 0.069) and 0.08 (95% CI 0.056; 0.105) higher BMIz as well as 0.001 (95% CI 0; 0.002) and 0.004 (95% CI 0.003; 0.005) with higher WtHr, respectively. Moreover, every 0.5-h delay in bedtime in non-school nights compared with school nights associated with 0.001 (95% CI 0; 0.002) greater increase in WtHr in the 2.5 years follow-up. Thus, a 2-h delay in bedtime at the age of 11 years corresponds with a 0.6 cm increase in waist circumference. The MR analysis did not indicate an opposite causal relationship: higher BMIz was not causing delayed bedtimes. Later bedtime on non-school days and discrepancy in bedtimes associated with increased BMIz and WtHr, while longitudinally these predicted higher WtHr, independently of sleep duration. Promoting early bedtimes, especially on weekends, should be considered in obesity prevention among school-aged children.
10.1111/jsr.13876
Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders.
Schizophrenia bulletin
BACKGROUND AND HYPOTHESIS:To identify promising drug targets for psychiatric disorders, we applied Mendelian randomization (MR) design to systematically screen blood metabolome for potential mediators of psychiatric disorders and further predict target-mediated side effects. STUDY DESIGN:We selected 92 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with totally 147 827 participants. Summary statistics for bipolar disorder (BIP), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), schizophrenia (SCZ), panic disorder (PD), autistic spectrum disorder (ASD), and anorexia nervosa (AN) originated from the Psychiatric Genomics Consortium, involving 1 143 340 participants. Mendelian randomization (MR) analyses were conducted to estimate associations of blood metabolites with psychiatric disorders. Phenome-wide MR analysis was further performed to predict side effects mediated by metabolite-targeted interventions. RESULTS:Eight metabolites were identified associated with psychiatric disorders, including five established mediators: N-acetylornithine (BIP: OR, 0.72 [95% CI, 0.66-0.79]; SCZ: OR, 0.74 [0.64-0.84]), glycine (BIP: OR, 0.62 [0.50-0.77]), docosahexaenoic acid (MDD: OR, 0.96 [0.94-0.97]), 3-Hydroxybutyrate (MDD: OR, 1.14 [1.08-1.21]), butyrylcarnitine (SCZ: OR, 1.22 [1.12-1.32]); and three novel mediators: 1-arachidonoylglycerophosphocholine (1-arachidonoyl-GPC)(BIP: OR, 0.31 [0.23-0.41]), glycoproteins (BIP: OR, 0.94 [0.92-0.97]), sphingomyelins (AN: OR, 1.12 [1.06-1.19]). Phenome-wide MR analysis showed that all identified metabolites except for N-acetylornithine and 3-Hydroxybutyrate had additional effects on nonpsychiatric diseases, while glycine, 3-Hydroxybutyrate, N-acetylornithine, and butyrylcarnitine had no adverse side effects. CONCLUSIONS:This MR study identified five established and three novel mediators for psychiatric disorders. N-acetylornithine, glycine, 3-Hydroxybutyrate, and butyrylcarnitine might be promising targets against psychiatric disorders with no predicted adverse side effects.
10.1093/schbul/sbac130
A genome-wide association study of frailty identifies significant genetic correlation with neuropsychiatric, cardiovascular, and inflammation pathways.
GeroScience
Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture.
10.1007/s11357-023-00771-z
Genetically predicted visceral adipose tissue and risk of nine non-tumour gastrointestinal diseases: evidence from a Mendelian randomization study.
International journal of obesity (2005)
BACKGROUND:Numerous studies have linked visceral adipose tissue (VAT) to gastrointestinal diseases. However, it remains unclear whether these associations reflect causal relationships. METHODS:We used a two-sample Mendelian randomization (MR) approach to elucidate the causal effect of VAT on nine non-tumour gastrointestinal diseases. The inverse-variance weighted method was used to perform the MR analyses. Complementary and multivariable MR analyses were performed to confirm the results. RESULTS:Genetically predicted higher VAT was associated with an increased risk of gastro-oesophageal reflux disease (GORD) (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.09-1.34; P = 3.06 × 10), duodenal ulcer (DU) (OR, 1.40; 95% CI, 1.10-1.77; P = 0.005), cholelithiasis (OR, 1.75; 95% CI, 1.53-2.00; P = 1.14 × 10), and non-alcoholic fatty liver disease (NAFLD) (OR, 2.68; 95% CI, 1.87-3.82; P = 6.26 × 10). There were suggestive associations between VAT and gastric ulcer (GU) (OR, 1.22; 95% CI, 1.01-1.48; P = 0.035) and acute pancreatitis (AP) (OR, 1.26; 95% CI, 1.05-1.52; P = 0.013). However, there was little evidence to support the associations between VAT and inflammatory bowel disease, irritable bowel syndrome, or chronic pancreatitis. The associations with GORD, GU, and NAFLD remained in the multivariable MR analyses with adjustment for body mass index (BMI). CONCLUSIONS:This study provided evidence in support of causal associations between VAT and GORD, GU, DU, cholelithiasis, AP, and NAFLD. Moreover, the associations between GORD, GU, and NAFLD were independent of the effect of BMI.
10.1038/s41366-023-01279-4
Associations Between Body Composition and Sensorineural Hearing Loss Among Adults Based on the UK Biobank.
Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
OBJECTIVE:To explore the association between body composition and sensorineural hearing loss (SNHL). STUDY DESIGN:Cross-sectional study, prospective study and Mendelian randomization (MR) analyses. SETTING:UK Biobank. METHODS:This cross-sectional study included 147,296 adult participants with complete data on body composition and the speech-reception-threshold (SRT) test. We further conducted a prospective study with 129,905 participants without SNHL at baseline and followed up to 15 years to explore the association between body composition and new-onset SNHL. Multivariable logistic regression and Cox regression models were used. Subgroup analyses stratified by age and sex were performed. We further assessed the causal association between body composition and SNHL using two-sample MR analyses. RESULTS:Our cross-sectional study revealed that fat percentage, especially leg (odds ratio [OR] 1.46, p = .029) and arm (OR 1.43, p = .004), were significant risk factors for SNHL. However, fat-free mass, especially in the arm (OR 0.27, p < .001) and leg (OR 0.58, p < .001) showed significant protective effects against SNHL, which was substantially consistent with the results of the prospective study. In addition, we found that young women with SNHL were more susceptible to body composition indicators. However, MR analyses revealed no evidence of significant causal association. CONCLUSION:Fat percentage, especially in the leg and arm, was a significant risk factor for SNHL, whereas fat-free mass, especially in the leg and arm, had significant protective effects against SNHL, however, these associations may not be causal.
10.1002/ohn.323
Plasma Concentrations of Calcium and Risk of Alzheimer Disease-Observational and Genetic Studies.
Clinical chemistry
BACKGROUND:Dysregulation of calcium ion homeostasis in neurons is well documented in Alzheimer disease (AD), and high plasma calcium concentrations have been associated with cognitive decline in the elderly; however, a potential causal nature for this association has not been elucidated. METHODS:Plasma calcium ion concentrations of 97 968 individuals from the Copenhagen General Population Study (CGPS) were included and multifactorial Cox regressions using splines or quartiles was performed to investigate the observational association. A plasma calcium ion genome-wide association study (GWAS) was performed in 2 independent subgroups of the CGPS. The plasma calcium ion GWAS and publicly available genomic data sets for plasma total calcium and AD were used to perform the currently most powerful 2-sample Mendelian randomization studies. RESULTS:The hazard ratio for lowest vs highest quartile of the calcium ion concentration was 1.24 (95% CI, 1.08-1.43) for AD. The plasma calcium ion GWAS identified 3 independent loci. None of the genetic instruments for plasma concentrations of calcium ions or total calcium were associated with AD risk. CONCLUSIONS:High plasma concentrations of calcium ions were observationally associated with increased risk of AD but genetic associations were not found, suggesting that the observational findings may be due to reverse causation or residual confounding.
10.1093/clinchem/hvad030
Causal relationship between particulate matter 2.5 and hypothyroidism: A two-sample Mendelian randomization study.
Frontiers in public health
Background:Epidemiological surveys have found that particulate matter 2.5 (PM) plays an important role in hypothyroidism. However, due to the methodological limitations of traditional observational studies, it is difficult to make causal inferences. In the present study, we assessed the causal association between PM concentrations and risk of hypothyroidism using two-sample Mendelian randomization (TSMR). Methods:We performed TSMR by using aggregated data from genome-wide association studies (GWAS) on the IEU Open GWAS database. We identified seven single nucleotide polymorphisms (SNPs) associated with PM concentrations as instrumental variables (IVs). We used inverse-variance weighting (IVW) as the main analytical method, and we selected MR-Egger, weighted median, simple model, and weighted model methods for quality control. Results:MR analysis showed that PM has a positive effect on the risk of hypothyroidism: An increase of 1 standard deviation (SD) in PM concentrations increases the risk of hypothyroidism by ~10.0% (odds ratio 1.10, 95% confidence interval 1.06-1.13, = 2.93E-08, by IVW analysis); there was no heterogeneity or pleiotropy in the results. Conclusion:In conclusion, increased PM concentrations are associated with an increased risk of hypothyroidism. This study provides evidence of a causal relationship between PM and the risk of hypothyroidism, so air pollution control may have important implications for the prevention of hypothyroidism.
10.3389/fpubh.2022.1000103
Causal Associations of PM2.5 and GDM: A Two-Sample Mendelian Randomization Study.
Toxics
Epidemiological studies have linked particulate matter (PM2.5) to gestational diabetes mellitus (GDM). However, the causality of this association has not been established; Mendelian randomization was carried out using summary data from genome-wide association studies (GWAS). For the analysis of the causal relationship between PM2.5 and GDM, the inverse variance weighted (IVW) method was used. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 423,796 European participants. The FinnGen consortium provided the GDM data, which included 6033 cases and 123,000 controls. We also performed multivariate MR (MVMR), adjusting for body mass index (BMI) and smoking. As a result, we found that each standard deviation increase in PM2.5 is associated with a 73.6% increase in the risk of GDM (OR: 1.736; 95%CI: 1.226-2.457). Multivariable MR analysis showed that the effect of PM2.5 on GDM remained after accounting for BMI and smoking. Our results demonstrate a causal relationship between PM2.5 and GDM.
10.3390/toxics11020171