- Title
- Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts
- Creator
- Ek, Weronica E.; Reznichenko, Anna; Holliday, Elizabeth G.; Houghton, Lesley; Gazouli, Maria; Karamanolis, George; Rappold, Gudrun; Burwinkel, Barbara; Surowy, Harald; Rafter, Joseph; Assadi, Ghazaleh; Li, Ling; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V.; Schmidt, Peter T.; Pedersen, Nancy L.; Magnusson, Patrik; Talley, Nicholas J.
- Relation
- Gut Vol. 64, Issue 11, p. 1774-1782
- Publisher Link
- http://dx.doi.org/10.1136/gutjnl-2014-307997
- Publisher
- BMJ Group
- Resource Type
- journal article
- Date
- 2015
- Description
- 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.
- Subject
- irritable bowel syndrome; genetics; genetic predisposition; genetic risks
- Identifier
- http://hdl.handle.net/1959.13/1332788
- Identifier
- uon:26934
- Identifier
- ISSN:1468-3288
- Language
- eng
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