IntroductionIrritable bowel syndrome (IBS) is a common gut-brain axis disorder characterized by abdominal pain and altered bowel habits, and it shows high comorbidity with psychiatric disorders. However, the shared genetic mechanisms underlying these associations remain incompletely understood.MethodsWe performed a large-scale meta-analysis of IBS in individuals of European ancestry by integrating genome-wide association study (GWAS) summary statistics from the UK Biobank, Bellygenes, and the Million Veteran Program (MVP), thereby increasing statistical power to detect novel IBS loci. We further conducted global genetic correlation analyses with psychiatric traits, followed by multi-trait analysis of GWAS (MTAG) and conditional false discovery rate (condFDR) analyses to identify pleiotropic loci. Transcriptomic, methylomic, and expression quantitative trait locus (eQTL) data were integrated to explore potential regulatory mechanisms.ResultsThe meta-analysis identified up to ten previously unreported IBS loci, several of which were supported by colonic and brain eQTL effects. Global genetic correlation analyses confirmed substantial genetic overlap between IBS and psychiatric traits, particularly major depressive disorder and neuroticism. MTAG and condFDR analyses uncovered more than 100 pleiotropic loci, including signals at SORCS1, SLC35D1, COA1, and TLE1. Integrative analyses of transcriptome- and methylome-wide data highlighted regulatory mechanisms spanning colonic, immune, and neuronal tissues, supporting neuro-immune crosstalk and mitochondrial involvement.DiscussionOur findings provide a comprehensive genetic characterization of IBS, refine its heritable basis, reveal pleiotropic links with psychiatric disorders, and implicate molecular pathways across the gut-brain axis. These results advance mechanistic understanding of IBS and may inform future therapeutic development for IBS and its psychiatric comorbidities.
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