Abstract

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

1. Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
2. Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Belgium.
3. University of Chicago, Department of Medicine, 5801 South Ellis, Chicago, Illinois 60637, USA.
4. Yale University, Departments of Medicine and Genetics, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, 300 Cedar Street, New Haven, Connecticut 06519, USA.
5. University of Pittsburgh, School of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center (UPMC) Presbyterian, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA.
6. University of Pittsburgh, Graduate School of Public Health, Department of Human Genetics, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
7. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.
8. The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
9. Johns Hopkins University, Department of Medicine, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, 1503 East Jefferson Street, Baltimore, Maryland 21231, USA.
10. Johns Hopkins University, Bloomberg School of Public Health, Department of Epidemiology, 615 E. Wolfe Street, Baltimore, Maryland 21205, USA.
11. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
12. Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, 8700 W. Beverly Blvd., Los Angeles, California 90048, USA.
13. Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1, Canada.
14. The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
15. University of Chicago, Department of Health Studies, 5841 S. Maryland Avenue, Chicago, Illinois 60637, USA.
16. Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
17. Centre National de Génotypage, Evry, France.
18. Unit of Hepatology and Gastroenterology, Department of Clinical Sciences, GIGA-R, Faculty of Medicine and CHU de Liège, University of Liège, Belgium.
19. Department of Gastroenterology, Clinique universitaire St Luc, UCL, Brussels, Belgium.
20. Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.
21. Department of Gastroenterology, University Hospital Leuven, Belgium.
22. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Belgium.
23. INSERM; Université Paris Diderot; Assistance Publique Hôpitaux de Paris; Hopital Robert Debré, Paris, France.
24. Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
25. Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, UK.
26. Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London, SE1 9RT, UK.
27. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
28. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
29. IBD research group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
30. Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
31. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, OX2 6HE, UK.
32. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
33. This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium.
34. A full list of authors is provided in the Supplementary Note online.

Correspondence to: Mark J Daly^8,32 e-mail: mjdaly@chgr.mgh.harvard.edu

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