Authors
Biagio Di Lorenzo, Leticia Camargo Tavares, Cristian Díaz-Muñoz, Francisco Heredia-Fernández, Isotta Bozzarelli, Cristina Esteban Blanco, Zhe Wang, Roelof A J Smit, Ruth J F Loos, Jibril Hirbo, Nancy J Cox, Peter Straub, Marie-Julie Favé, Philip Awadalla, Nikita Pozdeyev, Christopher R Gignoux, Colorado Center for Personalized Medicine, Daniel F Gudbjartsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Kari Stefansson, Erik Abner, Priit Palta, Estonian Biobank Research Team, Alexander T Williams, Kayesha Coley, Gerald Sze, Catherine John, Anne Richmond, Daniel McCartney, Caroline Hayward, Ashley J Mulford, Alan R Sanders, Raitis Peculis, Vita Rovite, Marija Simona Dombrovska, Mario Capasso, Valeria Lo Faro, Trishla Sinha, Esteban Alexander Lopera Maya, Alexandra Zhernakova, Lifelines Cohort, Ying Wang, Alicia Martin, Brett Vanderwerff, Sebastian Zöllner, Brian R Ferolito, Alexander C Pereira, John Michael Gaziano, Kelly Cho, Lanna Caruth, Lindsay Guare, Colleen M Kripke, Daniel J Rader, Shefali S Verma, Anurag Verma, Penn Medicine BioBank, Chadi Saad, Hamdi Mbarek, Pei-Yu Chao, Tzu-Ting Chen, Yen-Feng Lin, Yen-Chen Anne Feng, Prasanna K Challa, Hamed Khalili, Aristomo Andries, Eivind Ness-Jensen, Ben Michael Brumpton, Madhusudan Grover, FinnGen, Susanna Lemmelä, Serena Sanna, Ferdinando Bonfiglio, Mauro D'Amato
Published in
Gut. Jul 09, 2026. Epub Jul 09, 2026.
Abstract
Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight.
To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS.
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.
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.
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.
PMID:
42425734
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 4
- Comments 0