Weronica E Ek1, Anna Reznichenko1, Stephan Ripke2, Beate Niesler3, Marco Zucchelli1, Natalia V Rivera1, Peter T Schmidt4, Nancy L Pedersen5, Patrik Magnusson5, Nicholas J Talley6, Elizabeth G Holliday6, Lesley Houghton7, Maria Gazouli8, George Karamanolis9, Gudrun Rappold3, Barbara Burwinkel10, Harald Surowy10, Joseph Rafter1, Ghazaleh Assadi1, Ling Li1, Evangelia Papadaki1, Dario Gambaccini11, Santino Marchi11, Rocchina Colucci12, Corrado Blandizzi12, Raffaella Barbaro13, Pontus Karling14, Susanna Walter15, Bodil Ohlsson16, Hans Tornblom17, Francesca Bresso18, Anna Andreasson19, Aldona Dlugosz4, Magnus Simren17, Lars Agreus20, Greger Lindberg4, Guy Boeckxstaens21, Massimo Bellini11, Vincenzo Stanghellini13, Giovanni Barbara13, Mark J Daly2, Michael Camilleri22, Mira M Wouters21, Mauro D'Amato1. 1. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 2. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 3. Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany. 4. Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 6. Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia. 7. 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. 8. Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. 9. Academic Department of Gastroenterology, School of Medicine, University of Athens, Athens, Greece. 10. 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. 11. Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy. 12. Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy. 13. Department of Medical and Surgical Sciences, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy. 14. Department of Medicine, Umeå, University, Umeå, Sweden. 15. Division of Gastroenterology, Institution of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 16. Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden. 17. Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 18. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 19. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden Stress Research Institute, Stockholm University, Stockholm, Sweden. 20. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. 21. Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium. 22. Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Paul Enck; Qasim Aziz; Giovanni Barbara; Adam D Farmer; Shin Fukudo; Emeran A Mayer; Beate Niesler; Eamonn M M Quigley; Mirjana Rajilić-Stojanović; Michael Schemann; Juliane Schwille-Kiuntke; Magnus Simren; Stephan Zipfel; Robin C Spiller Journal: Nat Rev Dis Primers Date: 2016-03-24 Impact factor: 52.329