Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis

作者：Markos Tesfaye, Piotr Jahołkowski, Guy Hindley, Alexey Shadrin, Zillur Rahman, Shahram Bahrami, Aihua Lin, Børge Holen, Nadine Parker, Weiqiu Cheng, Linn Rødevand, Oleksandr Frei, Srdjan Djurovic, Anders M. Dale, Olav B. Smeland, Kevin S. O’Connell, Ole A. Andreassen · 发表于：Genome Medicine · 年份：2023 · DOI：10.1186/s13073-023-01212-4 · 被引用次数：45 · 研究领域：Gastrointestinal motility and disorders、Genetic Associations and Epidemiology、Gut microbiota and health

BACKGROUND: Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, and the genetic overlap with psychiatric and somatic disorders is not quantified beyond genome-wide genetic correlations. Here, we characterize the genetic architecture of IBS, further, investigate its genetic overlap with psychiatric and gastrointestinal phenotypes, and identify novel genomic risk loci. METHODS: Using GWAS summary statistics of IBS (53,400 cases and 433,201 controls), and psychiatric and gastrointestinal phenotypes, we performed bivariate casual mixture model analysis to characterize the genetic architecture and genetic overlap between these phenotypes. We leveraged identified genetic overlap to boost the discovery of genomic loci associated with IBS, and to identify specific shared loci associated with both IBS and psychiatric and gastrointestinal phenotypes, using the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework. We used functional mapping and gene annotation (FUMA) for functional analyses. RESULTS: IBS was highly polygenic with 12k trait-influencing variants. We found extensive polygenic overlap between IBS and psychiatric disorders and to a lesser extent with gastrointestinal diseases. We identified 132 independent IBS-associated loci (condFDR < 0.05) by conditioning on...