Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ulcerative colitis–risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Nature Genetics volume 41, pages 216–220 (2009)Cite this article

A Corrigendum to this article was published on 01 June 2009

This article has been updated

Abstract

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association signals and recombination rates for loci showing genome-wide significant association with UC.

Change history

  • 28 April 2009

    NOTE: In the first paragraph of the second column on the third page, rs11209026 A allele was incorrectly listed as rs111209026 A allele. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Xavier, R.J. & Podolsky, D.K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    Article  CAS  Google Scholar 

  2. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  Google Scholar 

  3. Libioulle, C. et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).

    Article  Google Scholar 

  4. Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    Article  CAS  Google Scholar 

  5. The Wellcome Trust Case Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  6. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830–832 (2007).

    Article  CAS  Google Scholar 

  7. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  8. Fisher, S.A. et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat. Genet. 40, 710–712 (2008).

    Article  CAS  Google Scholar 

  9. Franke, A. et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat. Genet. 40, 713–715 (2008).

    Article  CAS  Google Scholar 

  10. Kugathasan, S. et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat. Genet. 40, 1211–1215 (2008).

    Article  CAS  Google Scholar 

  11. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  Google Scholar 

  12. Stokkers, P.C., Reitsma, P.H., Tytgat, G.N. & van Deventer, S.J. HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis. Gut 45, 395–401 (1999).

    Article  CAS  Google Scholar 

  13. Luca, D. et al. On the use of general control samples for genome-wide association studies: genetic matching highlights causal variants. Am. J. Hum. Genet. 82, 453–463 (2008).

    Article  CAS  Google Scholar 

  14. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  15. Ewens, W.J. & Spielman, R.S. The transmission/disequilibrium test: history, subdivision, and admixture. Am. J. Hum. Genet. 57, 455–464 (1995).

    Article  CAS  Google Scholar 

  16. Makarova, K.S., Aravind, L. & Koonin, E.V. A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae. Trends Biochem. Sci. 25, 50–52 (2000).

    Article  CAS  Google Scholar 

  17. Murakami, M. et al. Arachidonate release and eicosanoid generation by group IIE phospholipase A(2). Biochem. Biophys. Res. Commun. 292, 689–696 (2002).

    Article  CAS  Google Scholar 

  18. Suzuki, N. et al. Structures, enzymatic properties, and expression of novel human and mouse secretory phospholipase A(2)s. J. Biol. Chem. 275, 5785–5793 (2000).

    Article  CAS  Google Scholar 

  19. Joazeiro, C.A. & Weissman, A.M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).

    Article  CAS  Google Scholar 

  20. Schoenborn, J.R. & Wilson, C.B. Regulation of interferon-gamma during innate and adaptive immune responses. Adv. Immunol. 96, 41–101 (2007).

    Article  CAS  Google Scholar 

  21. Aujla, S.J., Dubin, P.J. & Kolls, J.K. Th17 cells and mucosal host defense. Semin. Immunol. 19, 377–382 (2007).

    Article  CAS  Google Scholar 

  22. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Article  CAS  Google Scholar 

  24. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    Article  CAS  Google Scholar 

  25. Teller, I.C. & Beaulieu, J.F. Interactions between laminin and epithelial cells in intestinal health and disease. Expert Rev. Mol. Med. 3, 1–18 (2001).

    Article  CAS  Google Scholar 

  26. Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    Article  CAS  Google Scholar 

  27. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Article  Google Scholar 

  28. Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Thanks to L. Wu Datta, J. Fultz and J. Stempak for coordinating study subject recruitment, to A. Andriulli and O. Palmieri for providing clinical data and to J. Lian, A. Liew and H. Khalili for technical support. 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 (K.D.T.) and DK062429 (J.H.C.). The authors would also like to acknowledge additional support from the Atran Foundation (S.R.B.), Board of Governor's Chair in Medical Genetics at Cedars-Sinai Medical Center (J.I.R.), Bohmfalk Funds for Medical Research (J.H.C.), Burroughs Wellcome Medical Foundation (J.H.C.), Crohn's and Colitis Foundation of America (C.A., T.M.B., S.R.B., J.H.C., R.H.D., J.D.R.), Crohn's and Colitis Foundation of Canada (M.S.S.), Feintech Chair in Immunobiology (S.R.T.), Gale and Graham Wright Research Chair in Digestive Diseases (M.S.S.), Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center (T.M.B., S.R.B.), US National Institutes of Health grants RR00052 (S.R.B.), DK077905 (C.A.), DK068112 (J.-P.A.), DK072373 (J.H.C.), RR024139 (J.H.C.), DK076025 (R.H.D.), DK064869 (J.D.R.), MH057881 (K.R.), DK046763 (J.I.R., S.R.T., K.D.T.) and RR00425 (K.D.T.), the Rainin IBD Genetics Research Fund (J.-P.A.) and the W. Buford Lewis family (S.R.B.).

Author information

Author notes

  1. Mark S Silverberg and Judy H Cho: These authors contributed equally to this work

Authors and Affiliations

  1. Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Avenue, Toronto, M5G1X5, ON, Canada

    Mark S Silverberg & A Hillary Steinhart

  2. Department of Medicine, Section of Digestive Diseases, Yale University, 333 Cedar Street, LMP1080, New Haven, 06520, Connecticut, USA

    Judy H Cho, Clara Abraham & Deborah D Proctor

  3. Department of Genetics, Yale University, 333 Cedar Street, LMP1080, New Haven, 06520, Connecticut, USA

    Judy H Cho

  4. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montréal, H1T1C8, QC, Canada

    John D Rioux & Philippe Goyette

  5. Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, 90048, California, USA

    Dermot P B McGovern, Andrew F Ippoliti, Stephan R Targan, Jerome I Rotter & Kent D Taylor

  6. Department of Statistics, Carnegie Mellon University, Baker/Porter Hall A60K, Pittsburgh, 15213, Pennsylvania, USA

    Jing Wu & Kathryn Roeder

  7. IRCCS-CSS Hospital, Viale Cappuccini, 1, S. Giovanni Rotondo, Fg 71013, Italy

    Vito Annese, Fabrizio Bossa & Anna Latiano

  8. Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk A31, Cleveland, 44195, Ohio, USA

    Jean-Paul Achkar

  9. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, University of Pittsburgh School of Medicine, UPMC-PUH, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, 15213, Pennsylvania, USA

    Regan Scott, Miguel D Regueiro & Richard H Duerr

  10. Department of Public Health Sciences, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, M5G2M9, ON, Canada

    Wei Xu

  11. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Pittsburgh, 15261, Pennsylvania, USA

    M Michael Barmada & Richard H Duerr

  12. Department of Psychiatry, University of Pittsburgh Medical Center, 3811 O'Hara Street, Pittsburgh, 15213, Pennsylvania, USA

    Lambertus Klei

  13. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Mark J Daly

  14. Department of Medicine, Johns Hopkins University School of Medicine, Harvey M. and Lyn P. Meyerhoff Infammatory Bowel Disease Center, 600 N. Wolfe Street, Baltimore, 21287, Maryland, USA

    Theodore M Bayless & Steven R Brant

  15. Department of Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G1X8, ON, Canada

    Anne M Griffiths

  16. Department of Medicine, Université de Montréal and CHUM–Hôpital Saint-Luc, 1058, rue Saint-Denis, Montréal, H2X3J4, QC, Canada

    Raymond G Lahaie

  17. Division of Gastroenterology, Department of Medicine, Laval University, Quebec City, CHAUQ–Hôpital du St-Sacrement, 1050, Chemin Ste–Foy, G1S4L8, QC, Canada

    Pierre Paré

  18. Department of Health Studies, University of Chicago, 5841 S. Maryland Avenue, Chicago, 60637, Illinois, USA

    L Philip Schumm & Emily O Kistner

  19. The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, 11030, New York, USA

    Annette T Lee & Peter K Gregersen

  20. Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, 90048, California, USA

    Jerome I Rotter & Kent D Taylor

  21. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 1501 E. Jefferson Street, B136, Baltimore, 21231, Maryland, USA

    Steven R Brant

Authors
  1. Mark S Silverberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Judy H Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D Rioux
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dermot P B McGovern
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vito Annese
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Paul Achkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philippe Goyette
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Regan Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Michael Barmada
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lambertus Klei
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mark J Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Clara Abraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Theodore M Bayless
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Fabrizio Bossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Anne M Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Andrew F Ippoliti
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Raymond G Lahaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Anna Latiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Pierre Paré
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Deborah D Proctor
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Miguel D Regueiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. A Hillary Steinhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Stephan R Targan
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. L Philip Schumm
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Emily O Kistner
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Annette T Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Peter K Gregersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Jerome I Rotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Steven R Brant
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Kent D Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Kathryn Roeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Richard H Duerr
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.H.C., E.O.K. and L.P.S. developed and maintained the US National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium Data Coordinating Center infrastructure. C.A., J.-P.A., V.A., T.M.B., F.B., S.R.B., J.H.C., R.H.D., A.M.G., A.F.I., R.G.L., A.L., D.P.B.M., P.P., D.D.P., M.D.R., J.D.R., J.I.R., R.S., M.S.S., A.H.S., S.R.T. and K.D.T. provided clinical samples and information. S.R.B., J.H.C., M.J.D., R.H.D., P.K.G., A.T.L., J.D.R., J.I.R., M.S.S. and K.D.T. designed the GWAS. M.M.B. and R.H.D. performed quality control and preliminary association analyses of the GWAS data. J.W. performed the GEM, quantile-quantile and conditional analyses of the GWAS data under the supervision of K.R., with contributions from L.K. M.J.D. defined the 'best region' SNPs among SNPs with GWAS P < 0.0001. W.X. identified the best GWAS proxies for CD and UC loci. R.H.D., P.G., J.D.R. and R.S. designed and performed the replication study. R.H.D. and P.G. analyzed the replication data. The manuscript was written by J.H.C., R.H.D., K.R. and M.S.S. with contributions from C.A., M.M.B., S.R.B., P.K.G., D.P.B.M., J.D.R., J.I.R., R.S. and J.W. R.H.D. coordinated the genotyping, analysis and manuscript writing efforts of this multicenter study.

Corresponding author

Correspondence to Richard H Duerr.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–5, Supplementary Methods and Supplementary Note (PDF 1446 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Silverberg, M., Cho, J., Rioux, J. et al. Ulcerative colitis–risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41, 216–220 (2009). https://doi.org/10.1038/ng.275

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.275

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing