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

http://www.ncbi.nlm.nih.gov/pubmed/25248455?dopt=Abstract

2014 Sep 23. pii: gutjnl-2014-307997. doi: 10.1136/gutjnl-2014-307997. [Epub ahead of print]

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

Ek WE1, Reznichenko A1, Ripke S2, Niesler B3, Zucchelli M1, Rivera NV1, Schmidt PT4, Pedersen NL5, Magnusson P5, Talley NJ6, Holliday EG6, Houghton L7,Gazouli M8, Karamanolis G9, Rappold G3, Burwinkel B10, Surowy H10, Rafter J1, Assadi G1, Li L1, Papadaki E1, Gambaccini D11, Marchi S11, Colucci R12,Blandizzi C12, Barbaro R13, Karling P14, Walter S15, Ohlsson B16, Tornblom H17, Bresso F18, Andreasson A19, Dlugosz A4, Simren M17, Agreus L20, Lindberg G4, Boeckxstaens G21, Bellini M11, Stanghellini V13, Barbara G13, Daly MJ2, Camilleri M22, Wouters MM21, D'Amato M1.

Author information

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.

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