TY - JOUR
TI - Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts
AU - Ek, W.E.
AU - Reznichenko, A.
AU - Ripke, S.
AU - Niesler, B.
AU - Zucchelli, M.
AU - Rivera, N.V.
AU - Schmidt, P.T.
AU - Pedersen, N.L.
AU - Magnusson, P.
AU - Talley, N.J.
AU - Holliday, E.G.
AU - Houghton, L.
AU - Gazouli, M.
AU - Karamanolis, G.
AU - Rappold, G.
AU - Burwinkel, B.
AU - Surowy, H.
AU - Rafter, J.
AU - Assadi, G.
AU - Li, L.
AU - Papadaki, E.
AU - Gambaccini, D.
AU - Marchi, S.
AU - Colucci, R.
AU - Blandizzi, C.
AU - Barbaro, R.
AU - Karling, P.
AU - Walter, S.
AU - Ohlsson, B.
AU - Tornblom, H.
AU - Bresso, F.
AU - Andreasson, A.
AU - Dlugosz, A.
AU - Simren, M.
AU - Agreus, L.
AU - Lindberg, G.
AU - Boeckxstaens, G.
AU - Bellini, M.
AU - Stanghellini, V.
AU - Barbara, G.
AU - Daly, M.J.
AU - Camilleri, M.
AU - Wouters, M.M.
AU - D'Amato, M.
JO - Gut Pathogens
PY - 2015
VL - 64
TODO - 11
SP - 1774-1782
PB - BMJ Publishing Group
SN - 1757-4749
TODO - 10.1136/gutjnl-2014-307997
TODO - messenger RNA, adult;  Article;  controlled study;  female;  follow up;  gene expression;  gene function;  genetic association;  genetic risk;  genotype;  GRID2IP gene;  human;  irritable colon;  KDELR2 gene;  major clinical study;  male;  priority journal;  quality control;  quantitative trait locus;  questionnaire;  real time polymerase chain reaction;  rectum biopsy;  single nucleotide polymorphism;  Swedish citizen;  case control study;  clinical trial;  cohort analysis;  genetics;  international cooperation;  irritable colon;  middle aged;  multicenter study, Adult;  Case-Control Studies;  Cohort Studies;  Female;  Genome-Wide Association Study;  Humans;  Internationality;  Irritable Bowel Syndrome;  Male;  Middle Aged
TODO - 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. © 2015, BMJ Publishing Group. All rights reserved.
ER -