• An Erratum to this article was published on 29 March 2011

This article has been updated

Abstract

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan1, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10−5. Seven of these loci exceeded genome-wide significance (P < 5 × 10−8). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 × 10−8), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

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Change history

  • 29 March 2011

    In the version of this article initially published, Kathryn Roeder's affiliation was incorrect. Her correct affiliation is the Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This study was supported in part by US National Center for Research Resources (NCRR) grant M01-RR00425 to the Cedars-Sinai General Research Center Genotyping core; US National Institutes of Health/NIDDK grant P01-DK046763; Diabetes Endocrinology Research Center grant DK063491; Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. Additional funding was provided by grants DK76984 (M.C.D.) and DK084554 (M.C.D. and D.P.B.M.). Cardiovascular Health Study 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 and N01-HC-45133; grant numbers U01 HL080295 and R01 HL087652 from the US National Heart, Lung, and Blood Institute; and additional contribution from the US National Institute of Neurological Disorders and Stroke. A full list of principal Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. A.G. is supported by the Crohn's and Colitis Foundation of America. R.J.X. and M.J.D. are supported by grants DK83756, DK086502 and DK043351 (NIDDK).

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.B.M.) and DK062429 (J.H.C.). J.H.C. is also funded by Bohmfalk Funds for Medical Research, Burroughs Wellcome Medical Foundation and the Crohn's and Colitis Foundation of America. J.D.R. is also funded by grants from the US National Institute of Allergy and Infectious Diseases (AI065687; AI067152) and from the US National Institute of Diabetes and Digestive and Kidney Diseases (DK064869).

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 Singapore National Cancer Centre, Singapore General Hospital and the Singapore Millennium Foundation (to S.P.) and the Agency for Science Technology and Research (A*STAR), Singapore (to M.L.H. and M.S.). Genotyping and DNA handling at the Genome Institute of Singapore were performed by W.Y. Meah, K.K. Heng, H.B. Toh, X. Lin, S. Rajaram, D. Tan and C.H. Wong. We are grateful to the funders and investigators of the Epidemiological Investigation of Rheumatoid Arthritis for providing genotype data from healthy Swedish individuals.

Author information

Affiliations

  1. Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Dermot P B McGovern
    • , Phillip R Fleshner
    • , Marla C Dubinsky
    • , Andy Ippoliti
    • , Gil Y Melmed
    • , Eric A Vasiliauskas
    •  & Stephan R Targan
  2. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Agnès Gardet
    • , Chun Li
    •  & Ramnik J Xavier
  3. Department for Clinical Science Intervention and Technology, Karolinska Institutet and IBD Clinical Research Group at Karolinska University Hospital, Stockholm, Sweden.

    • Leif Törkvist
  4. Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada.

    • Philippe Goyette
    • , Caroline Lagacé
    • , Claudine Beauchamp
    •  & John D Rioux
  5. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jonah Essers
    • , Benjamin M Neale
    •  & Mark J Daly
  6. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Kent D Taylor
    • , Talin Haritunians
    •  & Jerome I Rotter
  7. Human Genetics, Genome Institute of Singapore, Singapore.

    • Rick T H Ong
    •  & Mark Seielstad
  8. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Todd Green
    • , Christine R Stevens
    • , Ramnik J Xavier
    •  & Mark J Daly
  9. Department of Medical Sciences, Gastroenterology Research Group, Uppsala University Hospital, Uppsala, Sweden.

    • Marie Carlson
  10. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Mauro D'Amato
  11. Division of Gastroenterology, Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.

    • Jonas Halfvarson
  12. Infectious Diseases, Genome Institute of Singapore, Singapore.

    • Martin L Hibberd
  13. Department of Medicine, and IBD Clinical Research Group at Karolinska University Hospital, Stockholm, Sweden.

    • Mikael Lördal
  14. Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm, Sweden.

    • Leonid Padyukov
  15. Gastroenterologia ed Endoscopia Digestiva, Ospedale 'Casa Sollievo della Sofferenza', Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.

    • Angelo Andriulli
    • , Elisabetta Colombo
    • , Anna Latiano
    • , Orazio Palmieri
    •  & Vito Annese
  16. Université de Montréal and Centre Hospitalier Universitaire de l'Université de Montréal, Montréal, Québec, Canada.

    • Edmond-Jean Bernard
  17. Department of Gastroenterology, Hôpital Sainte-Justine, Montréal, Québec, Canada.

    • Colette Deslandres
  18. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

    • Daan W Hommes
  19. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Dirk J de Jong
  20. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.

    • Pieter C Stokkers
  21. Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Rinse K Weersma
  22. Section of Digestive Diseases, Department of Medicine, Yale University, New Haven, Connecticut, USA.

    • Yashoda Sharma
    •  & Judy H Cho
  23. Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, Toronto, Ontario, Canada.

    • Mark S Silverberg
  24. Department of Genetics, Yale University, New Haven, Connecticut, USA.

    • Judy H Cho
  25. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

    • Jing Wu
    •  & Kathryn Roeder
  26. Johns Hopkins University School of Medicine, Department of Medicine, and Johns Hopkins University Bloomberg School of Public Health, Department of Epidemiology, Baltimore, Maryland, USA.

    • Steven R Brant
  27. Department of Health Studies, University of Chicago, Chicago, Illinois, USA.

    • L Phillip Schumm
  28. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  29. Cardiovascular Health Research Unit, Departments of Epidemiology and General Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    •  & David S Siscovick
  30. Department of Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.

    • Cisca Wijmenga
  31. Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.

    • Sven Pettersson
  32. Laboratory of Inflammation Biology, Singapore General Hospital, Singapore.

    • Sven Pettersson
  33. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

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

    • Mark Seielstad

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  1. The NIDDK IBD Genetics Consortium

    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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Contributions

D.P.B.M., M.J.D., R.J.X., J.D.R., J.H.C., P.G., R.H.D. and M.S. participated in the study design and conception. D.P.B.M., A.G., M.J.D., R.J.X., J.D.R. and M.S. wrote the manuscript with contributions from R.H.D. and J.I.R. D.P.B.M., L.T., K.D.T., C.Li, C.B., P.R.F., M.C., M.D., J.H., M.L.H., M.L., L.P., A.A., E.C., A.L., O.P., E.-J.B., C.D., D.W.H., D.J.d.J., P.C.S., R.K.W., Y.S., M.S.S., J.H.C., S.R.B., L.P.S., R.H.D., M.C.D., N.L.G., T.H., A.I., G.Y.M., D.S.S., E.A.V., S.R.T., V.A., C.W. and S.P. performed patient diagnosis, patient enrollment and collection of clinical data. Replication genotyping was performed by C. Lagacé, C.R.S. and C.B. in the laboratory of J.D.R. Expression analysis, immunohistochemistry and shRNA studies were designed by A.G. and R.J.X. and performed by C. Li and A.G. M.J.D., J.E., B.M.N., K.R., J.W., J.D.R., P.G., T.G. and R.T.H.O. provided statistical analyses. All authors contributed to the final paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dermot P B McGovern or John D Rioux or Mark Seielstad.

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DOI

https://doi.org/10.1038/ng.549

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