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Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Nature Genetics volume 43, pages 246252 (2011) | Download Citation

  • A Corrigendum to this article was published on 29 August 2011

This article has been updated

Abstract

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10−8), increasing the number of ulcerative colitis–associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

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Change history

  • 11 August 2011

    In the version of this article initially published, an affiliation was missing for two authors, Maria Gazouli and Nicholas P. Anagnou. They are also affiliated with the Foundation for Biomedical Research of the Academy of Athens in Athens, Greece. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

In memoriam to Marc Lémann, who dedicated his life to his patients but died too soon.

We thank all the 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, the Popgen biobank and infrastructure support through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence 'Inflammation at Interfaces'. Italian case collections were 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, University of Queensland (Ferguson Fellowship), National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). UK case collections were supported by the National Association for Colitis and Crohn's disease, Wellcome Trust, Medical Research Council UK and Peninsular College of Medicine and Dentistry, Exeter. Activities in Sweden were supported by the Swedish Society of Medicine, the Bengt Ihre Foundation, the Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, the Swedish Medical Research Council, the Soderbergh Foundation and the Swedish Cancer Foundation. Support for genotyping and genetic data analysis was provided by the Agency for Science Technology and Research (A*STAR), Singapore. We are grateful to the funders and investigators of the Epidemiological Investigation of Rheumatoid Arthritis for providing genotype data from healthy Swedish individuals.

The Wellcome Trust Case Control Consortium 2 project was supported by Wellcome Trust grant 083948/Z/07/Z. We also acknowledge the National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy's & St. Thomas' National Health Service (NHS) Trust, King's College London and to Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D.P.M.) and DK062429 (J.H.C.). J.H.C. is also funded by the Crohn's and Colitis Foundation of America; S.L.G. by DK069513 and Primary Children's Medical Center Foundation; and J.D.R. by US National Institutes of Health (NIH)/NIDDK grant DK064869. Cedars-Sinai is supported by National Center for Research Resources (NCRR) grant M01-RR00425, NIH/NIDDK grant P01-DK046763, DK 063491 and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. E.L., D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. S. Brand was supported by Deutsche Forschungsgemeinschaft (DFG BR 1912/5-1) and Else Kröner-Fresenius-Stiftung (P50/05/EKMS05/62). M.C. was supported by the Programme Hospitalier de Recherche Clinique. C.A.A. is supported by Wellcome Trust grant WT091745/Z/10/Z. J.C.B. is supported by Wellcome Trust grant WT089120/Z/09/Z. R.K.W. is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research (NWO). C.W. is supported by grants from the Celiac Disease Consortium (BSIK03009) and The Netherlands Organization for Scientific Research (NWO, VICI grant 918.66.620). L.H.v.d.B. acknowledges funding from the Prinses Beatrix Fonds, the Adessium Foundation and the Amyotrophic Lateral Sclerosis Association. L.F. received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). R.J.X. and A.N. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation.

Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd, Giuliani SpA, Shire PLC and Ferring Pharmaceuticals. We thank the 1958 British Birth Cohort and Banco Nacional deADN, Salamanca, Spain, who supplied control DNA samples. The IBSEN study group and the Norwegian Bone Marrow Donor Registry are acknowledged for contributing the Norwegian patient and control populations. The Cardiovascular Health Study (CHS) 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. We thank the members of the Quebec IBD Genetic Consortium, in particular A. Bitton, G. Aumais, E.J. Bernard, A. Cohen, C. Deslandres, R. Lahaie, D. Langelier and P. Paré. Other important contributors are K. Hanigan, N. Huang, P. Webb, D. Whiteman, A. Rutherford, R. Gwilliam, J. Ghori, D. Strachan, W. McCardle, W. Ouwehand, M. Newsky, S. Ehlers, I. Pauselius, K. Holm, C. Sina, M. Regueiro, A. Andriulli and M.C. Renda.

Author information

Author notes

    • Gabrielle Boucher
    • , Charlie W Lees
    • , Andre Franke
    •  & Mauro D'Amato

    These authors contributed equally to this work.

    • Hakon Hakonarson
    • , Graham Radford-Smith
    • , Richard H Duerr
    • , Séverine Vermeire
    •  & Rinse K Weersma

    These authors jointly supervised this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Carl A Anderson
    • , Suzannah Bumpstead
    • , James A B Floyd
    • , Katherine I Morley
    •  & Jeffrey C Barrett
  2. Université de Montréal, Medicine, Montréal, Québec, Canada.

    • Gabrielle Boucher
    • , Philippe Goyette
    • , Caroline Lagacé
    • , Gilles Jobin
    •  & John D Rioux
  3. Montreal Heart Institute, Research Center, Montréal, Québec, Canada.

    • Gabrielle Boucher
    • , Philippe Goyette
    • , Caroline Lagacé
    •  & John D Rioux
  4. University of Edinburgh, Western General Hospital, Gastrointestinal Unit, Molecular Medicine Centre, Edinburgh, UK.

    • Charlie W Lees
    •  & Jack Satsangi
  5. Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel, Germany.

    • Andre Franke
    • , David Ellinghaus
    •  & Stefan Schreiber
  6. Karolinska Institute, Department of Biosciences and Nutrition, Stockholm, Sweden.

    • Mauro D'Amato
  7. Cedars-Sinai Medical Center, Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA.

    • Kent D Taylor
    • , Dermot P McGovern
    •  & Stephan R Targan
  8. Addenbrooke's Hospital, University of Cambridge, Gastroenterology Research Unit, Cambridge, UK.

    • James C Lee
    •  & Miles Parkes
  9. The Children's Hospital of Philadelphia, Center for Applied Genomics, Philadelphia, Pennsylvania, USA.

    • Marcin Imielinski
  10. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy.

    • Anna Latiano
    • , Orazio Palmieri
    •  & Vito Annese
  11. University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh, Pennsylvania, USA.

    • Regan Scott
    • , Leonard Baidoo
    •  & Richard H Duerr
  12. Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, Belgium.

    • Leila Amininejad
  13. The Children's Hospital of Philadelphia, Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, Philadelphia, Pennsylvania, USA.

    • Robert N Baldassano
    •  & Hakon Hakonarson
  14. University of Otago, Department of Medicine, Christchurch, New Zealand.

    • Murray Barclay
    • , Rebecca Roberts
    •  & Richard Gearry
  15. Johns Hopkins University School of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Baltimore, Maryland, USA.

    • Theodore M Bayless
    •  & Steven R Brant
  16. University Hospital Munich, Department of Medicine II, Munich, Germany.

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

    • Carsten Büning
  18. Université de Lille Department of Hepato-Gastroenterology, Lille, France.

    • Jean-Frédéric Colombel
  19. Cincinnati Children's Hospital Medical Center, Pediatric Gastroenterology, Cincinnati, Ohio, USA.

    • Lee A Denson
  20. Ghent University Hospital, Department of Hepatology and Gastroenterology, Ghent, Belgium.

    • Martine De Vos
    •  & Debby Laukens
  21. Cedars-Sinai Medical Center, Department of Pediatrics, Los Angeles, California, USA.

    • Marla Dubinsky
  22. Torbay Hospital, Department of Gastroenterology, Torbay, Devon, UK.

    • Cathryn Edwards
  23. University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

    • Rudolf S N Fehrmann
    • , Lude Franke
    • , Cisca Wijmenga
    •  & Harm-Jan Westra
  24. Mater Health Services, Department of Gastroenterology, Brisbane, Australia.

    • Timothy Florin
  25. Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, Belgium.

    • Denis Franchimont
  26. University of Liège, Department of Genetics, Faculty of Veterinary Medicine, Liège, Belgium.

    • Michel Georges
  27. University of Washington, Cardiovascular Health Research Unit, Department of Internal Medicine, Seattle, Washington, USA.

    • Nicole L Glazer
  28. University of Utah School of Medicine, Department of Pediatrics, Salt Lake City, Utah, USA.

    • Stephen L Guthery
  29. Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA.

    • Talin Haritunians
    • , Dermot P McGovern
    •  & Jerome I Rotter
  30. Queensland Institute of Medical Research, Oncogenomics Laboratory, Brisbane, Australia.

    • Nicholas K Hayward
  31. Université Paris Diderot, Paris, France.

    • Jean-Pierre Hugot
  32. Hôpital Maisonneuve-Rosemont, Department of Gastroenterology, Montréal, Québec, Canada.

    • Gilles Jobin
  33. The University of Western Australia, School of Medicine and Pharmacology, Fremantle, Australia.

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

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

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

    • Cecile Libioulle
    •  & Edouard Louis
  37. Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy.

    • Monica Milla
    •  & Vito Annese
  38. Queensland Institute of Medical Research, Molecular Epidemiology, Brisbane, Australia.

    • Grant W Montgomery
    •  & Zhen Z Zhao
  39. Ninewells Hospital and Medical School, Department of Medicine, Dundee, UK.

    • Craig Mowat
    •  & Anne Phillips
  40. Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts, USA.

    • Aylwin Ng
    •  & Ramnik J Xavier
  41. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aylwin Ng
    •  & Ramnik J Xavier
  42. University of Manchester Department of Medical Genetics, Manchester, UK.

    • William Newman
  43. University Medical Center Utrecht, Department of Medical Genetics, Utrecht, The Netherlands.

    • Roel A Ophoff
  44. University of Florence, Institute of Human Genetics, Florence, Italy.

    • Laura Papi
  45. University Hospital of Nancy, Department of Hepato-Gastroenterology, Vandoeuvre-lès-Nancy, France.

    • Laurent Peyrin-Biroulet
  46. Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Department of Gastroenterology, Barcelona, Spain.

    • Julián Panés
  47. King's College London School of Medicine, Guy's Hospital, Department of Medical and Molecular Genetics, London, UK.

    • Natalie J Prescott
    •  & Christopher G Mathew
  48. Yale University, Section of Digestive Diseases, Department of Medicine, New Haven, Connecticut, USA.

    • Deborah D Proctor
    • , Yashoda Sharma
    •  & Judy H Cho
  49. Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK.

    • Richard Russell
    •  & David C Wilson
  50. University Hospital Gasthuisberg, Division of Gastroenterology, Leuven, Belgium.

    • Paul Rutgeerts
    •  & Séverine Vermeire
  51. Guy's & St. Thomas' NHS Foundation Trust, St. Thomas' Hospital, Department of Gastroenterology, London, UK.

    • Jeremy Sanderson
  52. Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Department of Gastroenterology, Barcelona, Spain.

    • Miquel Sans
  53. University of Chicago, Department of Health Studies, Chicago, Illinois, USA.

    • Philip Schumm
  54. University of Bern, Division of Gastroenterology, Inselspital, Bern, Switzerland.

    • Frank Seibold
  55. Queensland Institute of Medical Research, Inflammatory Bowel Diseases, Brisbane, Australia.

    • Lisa A Simms
    •  & Graham Radford-Smith
  56. Genome Institute of Singapore, Human Genetics, Singapore.

    • Mark Seielstad
  57. Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.

    • Mark Seielstad
  58. University of Toronto, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Toronto, Ontario, Canada.

    • A Hillary Steinhart
    •  & Mark S Silverberg
  59. Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Department of Neurology, Utrecht, The Netherlands.

    • Leonard H van den Berg
  60. Rikshospitalet University Hospital, Medical Department, Oslo, Norway.

    • Morten Vatn
    •  & Tom H Karlsen
  61. Leiden University Medical Center, Experimental Gastroenterology, Leiden, The Netherlands.

    • Hein Verspaget
  62. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Thomas Walters
    •  & Anne M Griffiths
  63. Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.

    • David C Wilson
  64. Academic Medical Center, Department of Gastroenterology, Amsterdam, The Netherlands.

    • Cyriel Y Ponsioen
  65. Viborg Regional Hospital, Medical Department, Viborg, Denmark.

    • Vibeke Andersen
  66. Karolinska Institutet, Department of Clinical Science Intervention and Technology, Stockholm, Sweden.

    • Leif Torkvist
  67. University of Athens, Department of Biology, School of Medicine, Athens, Greece.

    • Maria Gazouli
    •  & Nicholas P Anagnou
  68. Foundation for Biomedical Research of the Academy of Athens,, Athens, Greece.

    • Maria Gazouli
    •  & Nicholas P Anagnou
  69. Kaunas University of Medicine, Department of Gastroenterology, Kaunas, Lithuania.

    • Limas Kupcinskas
    •  & Jurgita Sventoraityte
  70. Newcastle University, Institute of Human Genetics, Newcastle upon Tyne, UK.

    • John C Mansfield
  71. Emory School of Medicine, Department of Genetics and Department of Pediatrics, Atlanta, Georgia, USA.

    • Subra Kugathasan
  72. Örebro University Hospital, Department of Medicine, Örebro, Sweden.

    • Jonas Halfvarson
  73. Peninsula College of Medicine and Dentistry, Barrack Road, Exeter, UK.

    • Tariq Ahmad
  74. INSERM, U1019, Lille, France.

    • Mathias Chamaillard
  75. Yale University, Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.

    • Judy H Cho
  76. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.

    • Stefan Schreiber
  77. Massachusetts General Hospital, Harvard Medical School, Center for Human Genetic Research, Boston, Massachusetts, USA.

    • Mark J Daly
  78. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon Hakonarson
  79. University of Pittsburgh Graduate School of Public Health, Department of Human Genetics, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  80. University Medical Center Groningen, Department of Gastroenterology, Groningen, The Netherlands.

    • Rinse K Weersma

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Contributions

C.W.L., A.F., K.D.T., J.C.L., M.I., A. Latiano, L.A., L.B., R.N.B., M.B., T.M.B., S. Brand, C.B., J.-F.C., L.A.D., M.D.V., M.D., C.E., R.S.N.F., T.F., D.F., M. Georges, J.G., N.L.G., S.L.G., T.H., N.K.H., J.-P.H., G.J., D.L., I.L., M.L., A. Levine, C. Libioulle, E.L., D.P.M., M.M., C.M., A.N., W.N., R.A.O., L.P., O.P., L.P.-B., J.P., A.P., N.J.P., D.D.P., R. Roberts, R. Russell, P.R., J. Sanderson, M. Sans, P.S., F.S., Y.S., M. Seielstad, A.H.S., S.R.T., L.H.v.d.B., M.V., H.V., T.W., C.W., D.C.W., H.-J.W., C.Y.P., V. Andersen, L.T., M. Gazouli, N.P.A., T.H.K., L.K., J. Sventoraityte, J.C.M., S.K., M.S.S., J.H., J.I.R., C.G.M., A.M.G., R.G., T.A., S.R.B., M.C., J. Satsangi, J.H.C., S.S., M.P., V. Annese, H.H., G.R.-S., R.H.D., S.V., R.K.W. and J.D.R. established DNA collections, recruited patients or assembled phenotypic data. A.F., M.D., P.G., C. Lagacé, R.S., S. Bumpstead, C. Libioulle, D.P.M., G.W.M., L.A.S., Z.Z.Z., M.C., R.H.D. and J.D.R. conducted or supervised laboratory work. C.A.A., G.B., D.E., J.A.B.F., L.F., K.I.M., A.N., R.A.O., R.J.X., M.J.D., J.C.B., R.K.W. and J.D.R. performed or supervised statistical analyses. C.A.A., G.B., C.W.L., G.R.-S., R.H.D., S.V., R.K.W. and J.D.R. drafted the manuscript. All authors read and approved the final manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carl A Anderson or John D Rioux.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1, 2, 4–6 and 8 and Supplementary Figures 1–3.

Excel files

  1. 1.

    Supplementary Table 3a

    Cohort specific results for all SNPs listed in Table 1 and Table 2

  2. 2.

    Supplementary Table 3b

    Cohort specific results for all SNPs included in follow-up phase, but failed our thresholds for follow-up

  3. 3.

    Supplementary Table 7

    Summary of candidate genes mapping from in silico analysis on the 47 UC loci

  4. 4.

    Supplementary Table 9

    Results from the International IBD Genetics Consortium CD and UC meta-analyses for the 99 loci reported for association in CD and/or UC

About this article

Publication history

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Published

DOI

https://doi.org/10.1038/ng.764

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