Relationship of cognition and Alzheimer’s disease with gastrointestinal tract disorders: a large-scale genetic overlap and Mendelian randomisation analysis

Abstract

Background Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, mechanisms underlying their relationships remain unclear. Leveraging several 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 GIT disorders. Method We assessed the global and local genetic correlation of ten cognitive traits (sample size [n] = 68,065–766,345) and AD (n = 455,258) with six GIT disorders (n = 332,601–456,327), using the linkage disequilibrium score regression (LDSC) and the Local Analysis of [co]Variant Association (LAVA) methods, respectively. We utilised the bidirectional two-sample Mendelian randomisation (MR) analysis method to investigate the potential causality between cognitive traits and GIT disorders. Also, we performed gene-based analyses and assessed the gene-level genetic overlap between cognitive traits and GIT disorders. Results LDSC reveals a strong and highly significant inverse global genetic correlation between all 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). LAVA detects 35 significant (P < 4.37 × 10− 5) bivariate local genetic correlations, across 14 loci, between cognitive traits, AD and GIT disorders (including IBD). MR analysis suggests a risk-decreasing causality of educational attainment, intelligence, cognitive performance and other cognitive traits on PUD, and GERD but not IBD. Also, we found a putative causal association of GERD with cognitive function decline. These findings were supported by other MR models and sensitivity analyses. Genes with nominal association (Pgene < 0.05) were significantly enriched (Pbinomial−test = 1.18 × 10− 3 – 2.20 × 10− 16), across GIT disorders (IBD inclusive), AD, and cognitive traits—evidence of gene-level genetic overlap. Conclusion Our study reveals highly significant negative global and local genetic correlations of all cognitive traits with all GIT disorders, except IBD. Findings highlights causally protective roles of cognitive traits on PUD, and GERD, and a putative causal association of GERD with cognitive function decline. Identified local genetic correlations enhance novel insights, especially, into IBD’s relationship with cognitive traits and AD, characterising important targets for further investigations.