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Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Nature Genetics 40, 955–962 (2008) | Download Citation

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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.

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References

  1. 1.

    New links to the pathogenesis of Crohn's disease provided by genome-wide association scans. Nat. Rev. Genet. 9, 9–14 (2008).

  2. 2.

    et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

  3. 3.

    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).

  4. 4.

    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).

  5. 5.

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

  6. 6.

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

  7. 7.

    et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

  8. 8.

    et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  9. 9.

    et al. A novel susceptibility locus for Crohn's disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4. PLoS Genet. 3, e58 (2007).

  10. 10.

    & 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

  11. 11.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  12. 12.

    et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).

  13. 13.

    et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

  14. 14.

    et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

  15. 15.

    et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat. Genet. 29, 223–228 (2001).

  16. 16.

    et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum. Mol. Genet. 14, 3499–3506 (2005).

  17. 17.

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

  18. 18.

    et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat. Genet. 36, 471–475 (2004).

  19. 19.

    et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007).

  20. 20.

    , , & Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29, 990–996 (1988).

  21. 21.

    et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).

  22. 22.

    et al. Enhanced production of monocyte chemotactic protein 3 in inflammatory bowel disease mucosa. Gut 44, 629–635 (1999).

  23. 23.

    Interleukin-18 and the pathogenesis of inflammatory diseases. Semin. Nephrol. 27, 98–114 (2007).

  24. 24.

    et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

  25. 25.

    & Integrating case-control and TDT studies. Ann. Hum. Genet. 69, 329–335 (2005).

  26. 26.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  27. 27.

    , , & Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

  28. 28.

    et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunology 1, 131–138 (2008).

  29. 29.

    et al. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer's patches. Immunity 24, 623–632 (2006).

  30. 30.

    et al. Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis. J. Leukoc. Biol. 82, 946–955 (2007).

  31. 31.

    et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

  32. 32.

    et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

  33. 33.

    et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).

  34. 34.

    et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).

  35. 35.

    et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

  36. 36.

    et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

  37. 37.

    et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

  38. 38.

    et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J. Immunol. 178, 4901–4907 (2007).

  39. 39.

    , , & Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J. Neurochem. 105, 1048–1056 (2008).

  40. 40.

    et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

  41. 41.

    et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 (2007).

  42. 42.

    et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

  43. 43.

    et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

  44. 44.

    et al. The expression and function of costimulatory molecules B7H and B7–H1 on colonic epithelial cells. Gastroenterology 126, 1347–1357 (2004).

  45. 45.

    et al. Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J. Exp. Med. 204, 105–115 (2007).

  46. 46.

    et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

  47. 47.

    et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

  48. 48.

    et al. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704–4710 (2007).

  49. 49.

    et al. Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall. J. Biol. Chem. 276, 23456–23463 (2001).

  50. 50.

    , , & Intelectin: a novel lipid raft-associated protein in the enterocyte brush border. Biochemistry 45, 9188–9197 (2006).

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Acknowledgements

We acknowledge use of DNA from the 1958 British Birth Cohort collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council (grant G0000934) and The Wellcome Trust (grant 068545/Z/02), and the UK Blood Services Collection of Common Controls (W. Ouwehand) funded by the Wellcome Trust. We also acknowledge the National Association for Colitis and Crohn's disease and the Wellcome Trust for supporting the case DNA collections, and support from UCB Pharma (unrestricted educational grant) and the NIHR Cambridge Biomedical Research Centre. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium is funded by the following grants: DK62431 (S.R.B.), DK62422 (J.H.C.), DK62420 (R.H.D.), DK62432 and DK064869 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.), NIH-AI06277 (R.J.X.) and DK62429 (J.H.C.). Additional support was provided by the Burroughs Wellcome Foundation (J.H.C.) and the Crohn's and Colitis Foundation of America (S.R.B., J.H.C.). We thank P. Gregersen and A. Lee (Feinstein Medical Research Institute) for their efforts and the use of control samples. This work was supported by grants from the DGTRE from the Walloon Region (n°315422 and CIBLES), the Communauté Française de Belgique (Biomod ARC), and the Belgian Science Policy organisation (SSTC Genefunc and Biomagnet PAI). E.L., S.Hansoul., D.F. and S.V. are fellows of the Belgian Fonds de la Recherche Scientifique (FNRS) and Fonds Wetenschappelijk Onderzoek-Vlaanderen (NFWO). C.S. is a fellow of the FRIA. We are grateful to all the clinicians, consultants and nursing staff who recruited subjects, including: J.-M. Maisin, V. Muls, J. Van Cauter, M. Van Gossum, P. Closset, P. Hayard and J.M. Ghilain (Erasme-BBIH-IBD); P. Mainguet, F. Mokaddem, F. Fontaine, J. Deflandre and H. Demolin (Ulg collaborators); J.-F. Colombel, M. Lemann, S. Almer, C. Tysk, Y. Finkel, M. Gassul, C. O'Morain, V. Binder and J.-P. Cézard (INSERM collaborators). Sincere thanks to L. Liang for his assistance in accessing the eQTL database, and to F. Merlin for expert technical assistance. Finally, we thank all individuals who contributed samples.

Author information

Affiliations

  1. Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Jeffrey C Barrett
    • , Lon R Cardon
    •  & Carl A Anderson

  2. Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Belgium.

    • Sarah Hansoul
    • , Cécile Libioulle
    • , Cynthia Sandor
    • , Myriam Mni
    •  & Michel Georges

  3. University of Chicago, Department of Medicine, 5801 South Ellis, Chicago, Illinois 60637, USA.

    • Dan L Nicolae

  4. Yale University, Departments of Medicine and Genetics, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, 300 Cedar Street, New Haven, Connecticut 06519, USA.

    • Judy H Cho
    •  & Michael T Murtha

  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.

    • Richard H Duerr
    •  & Miguel D Regueiro

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

    • Richard H Duerr
    •  & M Michael Barmada

  7. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.

    • John D Rioux

  8. The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • John D Rioux
    • , Todd Green
    •  & Mark J Daly

  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.

    • Steven R Brant
    • , Themistocles Dassopoulos
    •  & Lisa Wu Datta

  10. Johns Hopkins University, Bloomberg School of Public Health, Department of Epidemiology, 615 E. Wolfe Street, Baltimore, Maryland 21205, USA.

    • Steven R Brant

  11. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

    • Mark S Silverberg
    •  & A Hillary Steinhart

  12. Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, 8700 W. Beverly Blvd., Los Angeles, California 90048, USA.

    • Kent D Taylor
    • , Jerome I Rotter
    •  & Stephan R Targan

  13. Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1, Canada.

    • Alain Bitton

  14. The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.

    • Anne M Griffiths

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

    • Emily O Kistner
    •  & L Philip Schumm

  16. Gastrointestinal Unit and Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Ramnik J Xavier

  17. Centre National de Génotypage, Evry, France.

    • Mark Lathrop
    • , Ivo Gut
    • , Simon Heath
    •  & Diana Zelenika

  18. Unit of Hepatology and Gastroenterology, Department of Clinical Sciences, GIGA-R, Faculty of Medicine and CHU de Liège, University of Liège, Belgium.

    • Jacques Belaiche
    •  & Edouard Louis

  19. Department of Gastroenterology, Clinique universitaire St Luc, UCL, Brussels, Belgium.

    • Olivier Dewit

  20. Department of Hepatology and Gastroenterology, Ghent University Hospital, Belgium.

    • Debby Laukens
    •  & Martine de Vos

  21. Department of Gastroenterology, University Hospital Leuven, Belgium.

    • Paul Rutgeerts
    •  & Severine Vermeire

  22. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Belgium.

    • André Van Gossum
    •  & Denis Franchimont

  23. INSERM; Université Paris Diderot; Assistance Publique Hôpitaux de Paris; Hopital Robert Debré, Paris, France.

    • Jean-Pierre Hugot

  24. Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

    • Hazel Drummond
    • , Elaine Nimmo
    •  & Jack Satsangi

  25. Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, UK.

    • Tariq Ahmad

  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.

    • Natalie J Prescott
    • , Clive M Onnie
    • , Sheila A Fisher
    •  & Christopher G Mathew

  27. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.

    • Jonathan Marchini

  28. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Jilur Ghori
    • , Suzannah Bumpstead
    • , Rhian Gwilliam
    •  & Panos Deloukas

  29. IBD research group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.

    • Mark Tremelling
    •  & Miles Parkes

  30. Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.

    • John Mansfield

  31. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, OX2 6HE, UK.

    • Derek Jewell

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

    • Mark J Daly

Consortia

  1. the NIDDK IBD Genetics Consortium

    This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium

  2. the Belgian-French IBD Consortium

    This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium

  3. the Wellcome Trust Case Control Consortium

    This study is a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium. A full list of authors is provided in the Supplementary Note

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Correspondence to Mark J Daly.

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https://doi.org/10.1038/ng.175

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