Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

Weronica E. Ek, Anna Reznichenko, Stephan Ripke, Beate Niesler, Marco Zucchelli, Natalia V. Rivera, Peter T. Schmidt, Nancy L. Pedersen, Patrik Magnusson, Nicholas J. Talley, Elizabeth G. Holliday, Lesley Houghton, Maria Gazouli, George Karamanolis, Gudrun Rappold, Barbara Burwinkel, Harald Surowy, Joseph Rafter, Ghazaleh Assadi, Ling LiEvangelia Papadaki, Dario Gambaccini, Santino Marchi, Rocchina Colucci, Corrado Blandizzi, Raffaella Barbaro, Pontus Karling, Susanna Walter, Bodil Ohlsson, Hans Tornblom, Francesca Bresso, Anna Andreasson, Aldona Dlugosz, Magnus Simren, Lars Agreus, Greger Lindberg, Guy Boeckxstaens, Massimo Bellini, Vincenzo Stanghellini, Giovanni Barbara, Mark J. Daly, Michael Camilleri, Mira M. Wouters, Mauro D'Amato

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Objective: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design: We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10-6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

Original languageEnglish (US)
Pages (from-to)1774-1782
Number of pages9
Issue number11
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Gastroenterology


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