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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

Ek, Weronica E.; Reznichenko, Anna; Ripke, Stephan; Niesler, Beate; Zucchelli, Marco; Rivera, Natalia V.; Schmidt, Peter T.; Pedersen, Nancy L.; Magnusson, Patrik and Talley, Nicholas J., et al. (2015) In Gut 64(11). p.1774-1782
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... (More)
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 x 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. (Less)
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Gut
volume
64
issue
11
pages
1774 - 1782
publisher
BMJ Publishing Group
external identifiers
  • wos:000362593700016
  • scopus:84947569017
ISSN
1468-3288
DOI
10.1136/gutjnl-2014-307997
language
English
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yes
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7be36365-f977-43f5-8450-4f09a98a0a65 (old id 8206339)
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2015-12-01 07:06:37
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@article{7be36365-f977-43f5-8450-4f09a98a0a65,
  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 x 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.},
  author       = {Ek, Weronica E. and Reznichenko, Anna and Ripke, Stephan and Niesler, Beate and Zucchelli, Marco and Rivera, Natalia V. and Schmidt, Peter T. and Pedersen, Nancy L. and Magnusson, Patrik and Talley, Nicholas J. and Holliday, Elizabeth G. and Houghton, Lesley and Gazouli, Maria and Karamanolis, George and Rappold, Gudrun and Burwinkel, Barbara and Surowy, Harald and Rafter, Joseph and Assadi, Ghazaleh and Li, Ling and Papadaki, Evangelia and Gambaccini, Dario and Marchi, Santino and Colucci, Rocchina and Blandizzi, Corrado and Barbaro, Raffaella and Karling, Pontus and Walter, Susanna and Ohlsson, Bodil and Tornblom, Hans and Bresso, Francesca and Andreasson, Anna and Dlugosz, Aldona and Simren, Magnus and Agreus, Lars and Lindberg, Greger and Boeckxstaens, Guy and Bellini, Massimo and Stanghellini, Vincenzo and Barbara, Giovanni and Daly, Mark J. and Camilleri, Michael and Wouters, Mira M. and D'Amato, Mauro},
  issn         = {1468-3288},
  language     = {eng},
  number       = {11},
  pages        = {1774--1782},
  publisher    = {BMJ Publishing Group},
  series       = {Gut},
  title        = {Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts},
  url          = {http://dx.doi.org/10.1136/gutjnl-2014-307997},
  volume       = {64},
  year         = {2015},
}