A causal relationship between sarcopenia and cognitive impairment: A Mendelian randomization study.
PloS one
OBJECTIVE:Sarcopenia and cognitive impairment often coexist in the elderly. In this study, we investigated the causal relationship between sarcopenia-related muscle characteristics and cognitive performance. METHODS:We used linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR) analyses to estimate genetic correlations and causal relationships between genetically predicted sarcopenia-related muscle traits and cognitive function, as well as cognitive function-based discovery samples and replicated samples. Estimated effect sizes were derived from a fixed-effects meta-analysis. RESULTS:Our univariate genome-wide association study (GWAS) meta-analysis indicated a causal relationship between appendicular lean mass (ALM) (β = 0.049; 95% confidence interval (CI): 0.032-0.066, P < 0.001) and walking pace (β = 0.349; 95% CI: 0.210-0.487, P < 0.001) with cognitive function, where a causal relationship existed between ALM in both male and female (βALM-Male(M) = 0.060; 95% CI: 0.031-0.089, PALM-M < 0.001; βALM-Female(F) = 0.045; 95% CI: 0.020-0.069, PALM-F < 0.001) with cognitive function. Low grip strength was not causally associated with cognitive function (β = -0.045; 95% CI: -0.092 - -0.002, P = 0.062). A reverse causality GWAS meta-analysis showed a causal relationship between cognitive function and ALM (β = 0.033; 95% CI: 0.018-0.048, P < 0.001) and walking pace (β = 0.039; 95% CI: 0.033-0.051, P < 0.001), where ALM in both male and female showed a causality (βALM-M = 0.041; 95% CI: 0.019-0.063, PALM-M < 0.001; βALM-F = 0.034; 95% CI: 0.010-0.058, PALM-F = 0.005). Cognitive function was not causally related to low grip strength (β = -0.024; 95% CI: -0.073-0.025, P = 0.344). Multivariable MR1 (MVMR1) analyses showed a significant causal relationship for ALM (β = 0.077; 95% CI: 0.044-0.109, P = 0.000) and walking pace (β = 0.579; 95% CI: 0.383-0.775, P = 0.000) and cognitive function. Multivariable MR2 (MVMR2) multivariate analysis showed that ALM causality remained (β = 0.069; 95% CI: 0.033-0.106, P = 0.000), and walking pace (β = 0.589; 95% CI: 0.372-0.806, P = 0.000). CONCLUSIONS:Bidirectional two-sample MR demonstrated that sarcopenia-related muscle characteristics and cognitive performance were positive causal genetic risk factors for each other, while a multivariable MR study demonstrated that low ALM and a slow walking pace were causally involved in reduced cognitive performance. This study suggests a causal relationship between sarcopenia and cognitive impairment in older adults and provide new ideas for prevention and treatment.
10.1371/journal.pone.0309124
Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer.
Heliyon
Background:Observational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. Methods:Mendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. Results:Genetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127-1.1136, = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267-1.3153, = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694-1.2975, = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. Conclusions:Our study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.
10.1016/j.heliyon.2024.e35432
Relationship of Cognition and Alzheimer's Disease with Gastrointestinal Tract Disorders: A Large-Scale Genetic Overlap and Mendelian Randomisation Analysis.
International journal of molecular sciences
Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies’ summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer’s disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorders—peptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p < 4.37 × 10−5) bivariate local genetic correlations between cognitive traits, AD, and GIT disorders (including IBD). Mendelian randomisation analysis suggests a risk-decreasing causality of educational attainment, intelligence, and other cognitive traits on PUD and GERD, but not IBD, and a putative association of GERD with cognitive function decline. Gene-based analysis reveals a significant gene-level genetic overlap of cognitive traits with AD and GIT disorders (IBD inclusive, pbinomial-test = 1.18 × 10−3−2.20 × 10−16). Our study supports the protective roles of genetically-influenced educational attainments and other cognitive traits on the risk of GIT disorders and highlights a putative association of GERD with cognitive function decline. Findings from local genetic correlation analysis provide novel insights, indicating that the relationship of IBD with cognitive traits (and AD) will depend largely on their local effects across the genome.
10.3390/ijms232416199
Can early gut microbiota screening reduce the incidence of cognitive impairment? A Mendelian randomization study.
Journal of Alzheimer's disease : JAD
Gastrointestinal symptoms are now detected early in the clinical course of many dementia patients, and studies of the microbiome-gut-brain axis have confirmed bidirectional interactions between the gut and the brain. However, the causal relationship between gut microbiota and cognitive impairment has not been fully established. Therefore, this study conducted a bidirectional Mendelian randomization study to elucidate the potential causal relationship of gut microbiota to cognitive impairment. Using Mendelian randomization to identify gut flora with a genetic causal effect on the development of cognitive impairment. This study utilized publicly available genome-wide association study summary data to perform MR analysis, with gut microbiota as the exposure and various cognitive function indicators as well as scores for Alzheimer's disease as outcomes. This study selected single nucleotide polymorphisms as instrumental variables based on p-values, F-statistics, and r. Bidirectional Mendelian randomization was conducted using methods such as inverse variance weighted, MR-Egger, simple mode, and weighted mode to assess the causal relationship. Concurrently, this study carried out Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to identify potential heterogeneity and horizontal pleiotropy. This study identified a total of 31 gut microbes that have a causal relationship with cognitive impairment, which include 1 phylum, 4 classes, 3 orders, 2 families, and 21 genera. This study unveiled specific gut microbiota associated with cognitive impairment, offering new insights and approaches for the prevention and treatment of cognitive impairment through gut microbiota such as Bifidobacterium and Ruminococcus gnavus group.
10.3233/JAD-231457
The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis.
Biological psychiatry
BACKGROUND:Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence. METHODS:We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867). The inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. Considering the close relationship between brain volume and intelligence, we applied 2-step MR to evaluate whether the identified effect was mediated by regulating brain volume (N = 47,316). RESULTS:We found a risk effect of the genus Oxalobacter on intelligence (odds ratio = 0.968 change in intelligence per standard deviation increase in taxa; 95% CI, 0.952-0.985; p = 1.88 × 10) and a protective effect of the genus Fusicatenibacter on intelligence (odds ratio = 1.053; 95% CI, 1.024-1.082; p = 3.03 × 10). The 2-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partially mediated by regulating brain volume, with a mediated proportion of 33.6% (95% CI, 6.8%-60.4%; p = .014). CONCLUSIONS:Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.
10.1016/j.biopsych.2024.02.1012
Causal relationship of gut microbiota and metabolites on cognitive performance: A mendelian randomization analysis.
Neurobiology of disease
Emerging evidence has indicated that the alterations in gut microbiota and metabolites are associated with cognitive performance. However, whether these associations imply a causal relationship remains to be definitively established. Here, we conducted two-sample mendelian randomization (MR) studies to explore the causal effects of gut microbiota and metabolites on cognitive performance, using large-scale genome-wide association studies (GWASs). We identified seven positive causalities between host genetic-driven gut microbiota and cognitive performance, including Class Clostridia (p = 0.0002), Order Clostridiales (p = 8.12E-05), Family Rhodospirillaceae (p = 0.042) and Ruminococcustorquesgroup (p = 0.030), Dialister (p = 0.027), Paraprevotella (p = 0.037) and RuminococcaceaeUCG003 (p = 0.007) at the genus level. Additionally, a total of four higher abundance of gut microbiota traits were identified to be negatively related to cognitive performance, including genus Blautia (p = 0.013), LachnospiraceaeFCS020group (p = 0.035), LachnospiraceaeNK4A136group (p = 0.034) and Roseburia (p = 0.00016). In terms of plasma metabolites, we discovered eight positive and six negative relationships between genetic liability in metabolites and cognitive performance (all p < 0.05). No evidence was detected across a series of sensitivity analyses, including pleiotropy and heterogeneity. Collectively, our MR analyses revealed that gut microbiota and metabolites were causally connected with cognitive performance, which holds significant potential for shedding light on the early detection and diagnosis of cognitive impairment, offering valuable insights into this area of research.
10.1016/j.nbd.2023.106395