title: Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weronica E
authors.initials: WE
authors.lastname: Ek
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Reznichenko
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Niesler
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Zucchelli
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Rivera
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Magnusson
authors.affiliation: Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Talley
authors.affiliation: Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester, UK Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Houghton
authors.affiliation: Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Gazouli
authors.affiliation: Academic Department of Gastroenterology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Karamanolis
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.affiliation: Molecular Epidemiology Group, German Cancer Research Centre (DKFZ) Heidelberg, Heidelberg, Germany Division of Molecular Biology of Breast Cancer, Department of Gynaecology and Obstetrics, University Women's Clinic, University Heidelberg, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Molecular Epidemiology Group, German Cancer Research Centre (DKFZ) Heidelberg, Heidelberg, Germany Division of Molecular Biology of Breast Cancer, Department of Gynaecology and Obstetrics, University Women's Clinic, University Heidelberg, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Surowy
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rafter
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Papadaki
authors.affiliation: Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Gambaccini
authors.affiliation: Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
authors.forename: Santino
authors.initials: S
authors.lastname: Marchi
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.affiliation: Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Barbaro
authors.affiliation: Department of Medicine, Umeå, University, Umeå, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Karling
authors.affiliation: Division of Gastroenterology, Institution of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Walter
authors.affiliation: Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden.
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Tornblom
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bresso
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Andreasson
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aldona
authors.initials: A
authors.lastname: Dlugosz
authors.affiliation: Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Simren
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Agreus
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Boeckxstaens
authors.affiliation: Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Stanghellini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barbara
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium.
authors.forename: Mira M
authors.initials: MM
authors.lastname: Wouters
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D038622:Internationality; D043183:Irritable Bowel Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged
keywords: GENE EXPRESSION; GENETIC POLYMORPHISMS; GENETICS; IRRITABLE BOWEL SYNDROME