Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts. Issue 11 (23rd September 2014)

• Record Type: Journal Article
• Authors: Ek, Weronica E; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V; Schmidt, Peter T; Pedersen, Nancy L; Magnusson, Patrik; Talley, Nicholas J; Holliday, Elizabeth G; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Papadaki, Evangelia; Gambaccini, Dario; Marchi, Santino; Colucci, Rocchina; Blandizzi, Corrado; Barbaro, Raffaella; Karling, Pontus; Walter, Susanna; Ohlsson, Bodil; Tornblom, Hans; Bresso, Francesca; Andreasson, Anna; Dlugosz, Aldona; Simren, Magnus; Agreus, Lars; Lindberg, Greger; Boeckxstaens, Guy; Bellini, Massimo; Stanghellini, Vincenzo; Barbara, Giovanni; Daly, Mark J; Camilleri, Michael; Wouters, Mira M; D'Amato, Mauro;
• Is Part Of: Gut. Volume 64:Issue 11(2015)
• Page Start: 1774
• Page End: 1782
• Publication Date: 2014-09-23
• Subjects: IRRITABLE BOWEL SYNDROME -- GENETIC POLYMORPHISMS -- GENETICS -- GENE EXPRESSION; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2014-307997
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.