Letter | Published:

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

Nature Genetics volume 42, pages 11181125 (2010) | Download Citation


We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

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We thank all subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. This study was supported by the German Ministry of Education and Research through the National Genome Research Network and infrastructure support through the Deutsche Forschungsgemeinschaft cluster of excellence 'Inflammation at Interfaces' and by the Italian Ministry for Health GR-2008-1144485, with case collections supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition. We acknowledge funding provided by the Royal Brisbane and Women's Hospital Foundation; the University of Queensland (Ferguson Fellowship); the National Health and Medical Research Council, Australia, and by the European Community (Fifth Framework Program for Research and Development Technology) and by the European Crohn's and Colitis Organization. UK case collections were supported by the National Association for Colitis and Crohn's disease, Action Medical Research, Wellcome Trust, Medical Research Council UK, the University of Edinburgh and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge the National Institute of Health Research (NIHR) Biomedical Research Centre awards to Guy's & St. Thomas' National Health Service Trust/King's College London and to Addenbrooke's Hospital/University of Cambridge School of Clinical Medicine. The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 and DK064869 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.B.M.), DK76984 (M.J.D.) and DK084554 (M.J.D. and D.P.B.M.) and DK062429 (J.H.C.). J.H.C. is also funded by the Crohn's and Colitis Foundation of America, and S.L.G. is funded by DK069513 and the Primary Children's Medical Center Foundation. Cedars Sinai was supported by National Center for Research Resources (NCRR) grant M01-RR00425; US National Institutes of Health/NIDDK grant P01-DK046763; DK 063491; and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. R.K.W. is supported by a clinical fellow grant (90700281) from The Netherlands Organization for Scientific Research. E.L., D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. S.B. was supported by the Deutsche Forschungsgemeinschaft (DFG; BR 1912/5-1). J.C. Barrett is supported by Wellcome Trust grant WT089120/Z/09/Z. Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd. and Giuliani SpA. We acknowledge the Wellcome Trust Case Control Consortium. We thank the 1958 British Birth Cohort and Banco Nacional de ADN, Salamanca, Spain, who supplied control DNA samples. The Cardiovascular Health Studies research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Other significant contributors were K. Hanigan, Z.-Z. Zhao, N. Huang, P. Webb, N. Hayward, A. Rutherford, R. Gwilliam, J. Ghori, D. Strachan, W. McCardle, W. Ouwehand, M. Newsky, S. Ehlers, I. Pauselius, K. Holm, C. Sina, L. Baidoo, A. Andriulli and M.C. Renda.

Author information

Author notes

    • Andre Franke
    • , Dermot P B McGovern
    •  & Jeffrey C Barrett

    These authors contributed equally to this work.

    • Mark J Daly
    •  & Miles Parkes

    These authors jointly directed this project.


  1. Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.

    • Andre Franke
    • , David Ellinghaus
    •  & Stefan Schreiber
  2. Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Dermot P B McGovern
    •  & Stephan R Targan
  3. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Dermot P B McGovern
    • , Talin Haritunians
    • , Jerome I Rotter
    •  & Kent D Taylor
  4. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Jeffrey C Barrett
    • , Carl A Anderson
    • , Suzanne Bumpstead
    •  & Luke Jostins
  5. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Kai Wang
    •  & Hakon Hakonarson
  6. Inflammatory Bowel Disease Research Group, Queensland Institute of Medical Research, Brisbane, Australia.

    • Graham L Radford-Smith
    •  & Lisa A Simms
  7. Peninsula College of Medicine and Dentistry, Exeter, UK.

    • Tariq Ahmad
  8. Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Charlie W Lees
    •  & Jack Satsangi
  9. PopGen Biobank, Christian-Albrechts University Kiel, Kiel, Germany.

    • Tobias Balschun
  10. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • James Lee
    •  & Miles Parkes
  11. Department of Medicine, University of Otago, Christchurch, New Zealand.

    • Rebecca Roberts
    • , Murray Barclay
    •  & Richard Gearry
  12. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
  13. Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.

    • Eleonora M Festen
    •  & Cisca Wijmenga
  14. Department of Genetics, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

    • Michel Georges
  15. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Todd Green
    • , Soumya Raychaudhuri
    •  & Mark J Daly
  16. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy.

    • Anna Latiano
    •  & Vito Annese
  17. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Natalie J Prescott
  18. Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia.

    • Grant W Montgomery
    •  & David Whiteman
  19. Department of Health Studies, University of Chicago, Chicago, Illinois, USA.

    • Philip Schumm
  20. Section of Digestive Diseases, Department of Medicine, Yale University, New Haven, Connecticut, USA.

    • Yashoda Sharma
    • , Deborah D Proctor
    •  & Judy H Cho
  21. Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Robert N Baldassano
    •  & Hakon Hakonarson
  22. Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Theodore M Bayless
    •  & Steven R Brant
  23. Department of Medicine II, University Hospital Munich Grosshadern, Ludwig-Maximilians-University, Munich, Germany.

    • Stephan Brand
    •  & Jürgen Glas
  24. Department of Gastroenterology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany.

    • Carsten Büning
  25. Montreal Jewish General Hospital, Montréal, Québec, Canada.

    • Albert Cohen
  26. Registre des Maladies Inflammatoires du Tube Digestif du Nord-Ouest de la France (EPIMAD), Université de Lille, Lille, France.

    • Jean-Frederick Colombel
  27. Unit of Gastroenterology, Cervello Hospital, Palermo, Italy.

    • Mario Cottone
  28. Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile (ENEA), Department of Biology of Radiations and Human Health, Rome, Italy.

    • Laura Stronati
  29. Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Ted Denson
  30. Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.

    • Martine De Vos
    •  & Debby Laukens
  31. Division of Gastroenterology, University Hospital Padua, Padua, Italy.

    • Renata D'Inca
  32. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California, USA.

    • Marla Dubinsky
  33. Torbay Hospital, Torbay, Devon, UK.

    • Cathryn Edwards
  34. Department of Gastroenterology, Mater Health Services, Brisbane, Australia.

    • Tim Florin
  35. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium.

    • Denis Franchimont
    •  & Andre Van Gossum
  36. Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany.

    • Jürgen Glas
  37. Department of Human Genetics, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.

    • Jürgen Glas
  38. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Stephen L Guthery
  39. Department of Medicine, Örebro University Hospital, Örebro, Sweden.

    • Jonas Halfvarson
  40. Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.

    • Hein W Verspaget
  41. Université Paris Diderot, Paris, France.

    • Jean-Pierre Hugot
  42. Department of Gastroenterology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

    • Amir Karban
  43. School of Medicine and Pharmacology, The University of Western Australia, Fremantle, Australia.

    • Ian Lawrance
  44. GETAID group, Université Paris Diderot, Paris, France.

    • Marc Lemann
  45. Pediatric Gastroenterology Unit, Wolfson Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Arie Levine
  46. Division of Gastroenterology, Centre Hospitalier Universitaire, Université de Liège, Liège, Belgium.

    • Cecile Libioulle
    •  & Edouard Louis
  47. Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.

    • Craig Mowat
    •  & Anne Phillips
  48. Department of Medical Genetics, University of Manchester, Manchester, UK.

    • William Newman
  49. Department of Gastroenterology, Hospital Clínic/Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER EHD), Barcelona, Spain.

    • Julián Panés
    •  & Miquel Sans
  50. Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Miguel Regueiro
    •  & Richard H Duerr
  51. Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK.

    • Richard Russell
  52. Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Paul Rutgeerts
    •  & Severine Vermeire
  53. Department of Gastroenterology, Guy's and St Thomas' National Health Service Foundation Trust, St Thomas' Hospital, London, UK.

    • Jeremy Sanderson
  54. Division of Gastroenterology, Inselspital, University of Bern, Bern, Switzerland.

    • Frank Seibold
  55. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada.

    • A Hillary Steinhart
    •  & Mark S Silverberg
  56. Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

    • Pieter C F Stokkers
  57. Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

    • Leif Torkvist
  58. Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.

    • Gerd Kullak-Ublick
  59. Child Life and Health, University of Edinburgh, Edinburgh, UK.

    • David Wilson
  60. The Hospital for Sick Children, University of Toronto, Ontario, Canada.

    • Thomas Walters
    •  & Anne M Griffiths
  61. Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.

    • John D Rioux
  62. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Mauro D'Amato
  63. Department of Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands.

    • Rinse K Weersma
  64. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Subra Kugathasan
  65. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.

    • John C Mansfield
  66. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  67. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.

    • Stefan Schreiber
  68. Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.

    • Judy H Cho
  69. Unit of Gastroenterology, University Hospital Careggi, Florence, Italy.

    • Vito Annese


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A.F., D.P.B.M., G.L.R.-S., T.A., J.L., R. Roberts, J.C. Bis, T.H., A. Latiano, C.G.M., N.J.P., J.I.R., P.S., Y.S., L.A.S., K.D.T., D. Whiteman, C.W., G.K.-U., J.D.R., M.D.'A., R.K.W., S.V., R.H.D., J. Satsangi, S.S., V.A., H.H. and M.P. were involved in establishing DNA collections and/or assembling phenotypic data. A.F., D.E., J.C. Barrett, K.W., T.G., S.R., C.A.A., L.J. and M.J.D. performed statistical analyses. D.P.B.M., G.L.R.-S., C.W.L., E.M.F., R.N.B., M.B., T.M.B., S. Brand, C.B., A.C., J.-F.C., M.C., L.S., T.D., M.D.V., R.D.'I., M.D., C.E., T.F., D.F., A.M.G., R.G., J.G., A.V.G., S.L.G., J.H., H.W.V., J.-P.H., A.K., D.L., I.L., M.L., A. Levine, C.L., E.L., C.M., W.N., J.P., A.P., D.D.P., M.R., P.R., R. Russell, J. Satsangi, M.S.S., M.S., F.S., A.H.S., P.C.F.S., S.R.T., L.T., T.W., S.R.B., R.K.W., S.K., A.M.G., J.C.M., S.V., D. Wilson, R.H.D., M.S., J. Sanderson, S.S., J.H.C., V.A. and M.P. recruited patients. A.F., D.P.B.M., T.B., S. Bumpstead, J.I.R., M.G. and G.W.M. supervised laboratory work. A.F., D.P.B.M., J.C. Barrett, K.W., S. Brand, R.H.D., J. Satsangi, S.S., J.H.C., M.J.D. and M.P. contributed to writing the manuscript. All authors read and approved the final manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Miles Parkes.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–6, Supplementary Figures 1–4 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 3

    Odds ratios (OR) and risk allele frequencies (RAF) for the 71 SNPs listed in Tables 1 and 2

  2. 2.

    Supplementary Table 4

    Raw allele counts and empirical variance for the 71 SNPs listed in Tables 1 and 2

  3. 3.

    Supplementary Table 6

    Positional candidate genes mapping within regions of confirmed association with Crohn's disease

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