Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.
2015 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, 1774-1782 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2015. Vol. 64, 1774-1782 p.
Gastroenterology and Hepatology Medical Genetics
IdentifiersURN: urn:nbn:se:liu:diva-112750DOI: 10.1136/gutjnl-2014-307997ISI: 000362593700016PubMedID: 25248455OAI: oai:DiVA.org:liu-112750DiVA: diva2:771059