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Original article
Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts
  1. Weronica E Ek1,
  2. Anna Reznichenko1,
  3. Stephan Ripke2,3,
  4. Beate Niesler4,
  5. Marco Zucchelli1,
  6. Natalia V Rivera1,
  7. Peter T Schmidt5,
  8. Nancy L Pedersen6,
  9. Patrik Magnusson6,
  10. Nicholas J Talley7,
  11. Elizabeth G Holliday7,
  12. Lesley Houghton8,9,
  13. Maria Gazouli10,
  14. George Karamanolis11,
  15. Gudrun Rappold4,
  16. Barbara Burwinkel12,13,
  17. Harald Surowy12,13,
  18. Joseph Rafter1,
  19. Ghazaleh Assadi1,
  20. Ling Li1,
  21. Evangelia Papadaki1,
  22. Dario Gambaccini14,
  23. Santino Marchi14,
  24. Rocchina Colucci15,
  25. Corrado Blandizzi15,
  26. Raffaella Barbaro16,
  27. Pontus Karling17,
  28. Susanna Walter18,
  29. Bodil Ohlsson19,
  30. Hans Tornblom20,
  31. Francesca Bresso1,5,
  32. Anna Andreasson21,22,
  33. Aldona Dlugosz5,
  34. Magnus Simren20,
  35. Lars Agreus21,
  36. Greger Lindberg5,
  37. Guy Boeckxstaens23,
  38. Massimo Bellini14,
  39. Vincenzo Stanghellini16,
  40. Giovanni Barbara16,
  41. Mark J Daly2,3,
  42. Michael Camilleri24,
  43. Mira M Wouters23,
  44. Mauro D'Amato1
  1. 1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  2. 2Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  4. 4Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
  5. 5Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
  6. 6Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  7. 7Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
  8. 8Faculty of Medical and Human Sciences, Institute of Inflammation and Repair, University of Manchester, Manchester, UK
  9. 9Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
  10. 10Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece
  11. 11Academic Department of Gastroenterology, School of Medicine, University of Athens, Athens, Greece
  12. 12Molecular Epidemiology Group, German Cancer Research Centre (DKFZ) Heidelberg, Heidelberg, Germany
  13. 13Division of Molecular Biology of Breast Cancer, Department of Gynaecology and Obstetrics, University Women's Clinic, University Heidelberg, Heidelberg, Germany
  14. 14Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
  15. 15Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy
  16. 16Department of Medical and Surgical Sciences, University of Bologna, St. Orsola—Malpighi Hospital, Bologna, Italy
  17. 17Department of Medicine, Umeå, University, Umeå, Sweden
  18. 18Division of Gastroenterology, Institution of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  19. 19Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden
  20. 20Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  21. 21Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
  22. 22Stress Research Institute, Stockholm University, Stockholm, Sweden
  23. 23Translational Research Center for Gastrointestinal Disorders, Leuven University, Leuven, Belgium
  24. 24Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Mauro D'Amato, Department of Biosciences and Nutrition, Karolinska Institutet, Halsovag 7-9, Stockholm SE-14183, Sweden; mauro.damato{at}


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.


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