1 Department of Medicine and Surgery, LUM University, Casamassima, Italy.
2 National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australian Capital Territory, Australia.
3 Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
4 Gastroenterology Unit, Massachusetts General Hospital, Boston, MA, USA.
5 Clinical Translational Epidemiology Unit, Mongan Institute, Massachusetts General Hospital, Boston, MA, USA.
6 Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain.
7 Department of Epidemiology, University of Alabama at Birmingham Health System, Birmingham, AL, USA.
8 Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10 Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
11 Vanderbilt Genetic Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
12 Centre for Structural and Functional Genomics, Department of Biology, Concordia University, Montréal, Quebec, Canada.
13 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
14 Molecular Genetics, University of Oxford, Oxford, UK.
15 Big Data Institute, Nuffield Department of Health, University of Oxford, Oxford, UK.
16 Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, CO, USA.
17 Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz, Aurora, CO, USA.
18 Colorado Center for Personalized Medicine, University of Colorado Anschutz, Aurora, CO, USA.
19 University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, CO, USA.
20 Human Medical Genetics and Genomics Program, University of Colorado Anschutz, Aurora, CO, USA.
21 Amgen deCODE Genetics, Reykjavik, Iceland.
22 School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
23 Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
24 Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
25 Division of Public Health and Epidemiology, School of Medical Sciences, University of Leicester, Leicester, UK.
26 University Hospitals of Leicester NHS Trust, Leicester, UK.
27 Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
28 Genomic Health Initiative, Endeavor Health, Evanston, IL, USA.
29 Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
30 Latvian Biomedical Research and Study Centre, Riga, Latvia.
31 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
32 CEINGE Biotecnologie Avanzate Franco Salvatore s.c.a r.l, Naples, Italy.
33 Institute for Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
34 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
35 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
36 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
37 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
38 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
39 Department of Biostatistics and Center for Statistical Genetics, University of Michigan School

Background: Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight.

Objective: To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS.

Design: We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets.

Results: Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts.

Conclusions: This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.