PT  - JOURNAL ARTICLE
AU  - Weronica E Ek
AU  - Anna Reznichenko
AU  - Stephan Ripke
AU  - Beate Niesler
AU  - Marco Zucchelli
AU  - Natalia V Rivera
AU  - Peter T Schmidt
AU  - Nancy L Pedersen
AU  - Patrik Magnusson
AU  - Nicholas J Talley
AU  - Elizabeth G Holliday
AU  - Lesley Houghton
AU  - Maria Gazouli
AU  - George Karamanolis
AU  - Gudrun Rappold
AU  - Barbara Burwinkel
AU  - Harald Surowy
AU  - Joseph Rafter
AU  - Ghazaleh Assadi
AU  - Ling Li
AU  - Evangelia Papadaki
AU  - Dario Gambaccini
AU  - Santino Marchi
AU  - Rocchina Colucci
AU  - Corrado Blandizzi
AU  - Raffaella Barbaro
AU  - Pontus Karling
AU  - Susanna Walter
AU  - Bodil Ohlsson
AU  - Hans Tornblom
AU  - Francesca Bresso
AU  - Anna Andreasson
AU  - Aldona Dlugosz
AU  - Magnus Simren
AU  - Lars Agreus
AU  - Greger Lindberg
AU  - Guy Boeckxstaens
AU  - Massimo Bellini
AU  - Vincenzo Stanghellini
AU  - Giovanni Barbara
AU  - Mark J Daly
AU  - Michael Camilleri
AU  - Mira M Wouters
AU  - Mauro D'Amato
TI  - Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts
AID  - 10.1136/gutjnl-2014-307997
DP  - 2015 Nov 01
TA  - Gut
PG  - 1774--1782
VI  - 64
IP  - 11
4099  - http://gut.bmj.com/content/64/11/1774.short
4100  - http://gut.bmj.com/content/64/11/1774.full
SO  - Gut2015 Nov 01; 64
AB  - 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.