Letter | Published:

Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Nature volume 491, pages 119124 (01 November 2012) | Download Citation

Abstract

Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations1. Genome-wide association studies and subsequent meta-analyses of these two diseases2,3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Data deposits

Data have been deposited in the NCBI database of Genotypes and Phenotypes under accession numbers phs000130.v1.p1 and phs000345.v1.p1. Summary statistics for imputed GWAS are available at http://www.broadinstitute.org/mpg/ricopili/. Summary statistics for the meta-analysis markers are available at http://www.ibdgenetics.org/. The 523 causal gene network Cytoscape file is available on request.

References

  1. 1.

    et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012)

  2. 2.

    et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genet. 43, 246–252 (2011)

  3. 3.

    et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010)

  4. 4.

    , & Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011)

  5. 5.

    & Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med. 365, 1612–1623 (2011)

  6. 6.

    & Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13, 101 (2011)

  7. 7.

    , , & The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl Acad. Sci. USA 109, 1193–1198 (2012)

  8. 8.

    et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009)

  9. 9.

    et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)

  10. 10.

    et al. Primary immunodeficiencies: 2009 update. J. Allergy Clin. Immunol. 124, 1161–1178 (2009)

  11. 11.

    , , , & Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann. NY Acad. Sci. 1246, 92–101 (2011)

  12. 12.

    , , & Genetically determined susceptibility to mycobacterial infection. J. Clin. Pathol. 61, 1006–1012 (2008)

  13. 13.

    et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nature Genet. 43, 1247–1251 (2011)

  14. 14.

    et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007)

  15. 15.

    et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007)

  16. 16.

    et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009)

  17. 17.

    et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011)

  18. 18.

    & A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, Article 17 (2005)

  19. 19.

    et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res. 21, 1008–1016 (2011)

  20. 20.

    et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008)

  21. 21.

    et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008)

  22. 22.

    et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)

  23. 23.

    et al. Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes. PLoS Genet. 6, e1000932 (2010)

  24. 24.

    et al. Increasing the power to detect causal associations by combining genotypic and expression data in segregating populations. PLOS Comput. Biol. 3, e69 (2007)

  25. 25.

    , & Meta-analysis of vitamin D receptor polymorphisms and pulmonary tuberculosis risk. Int. J. Tuberc. Lung Dis. 9, 1174–1177 (2005)

  26. 26.

    et al. SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and meta-analysis. PLoS ONE 6, e15831 (2011)

  27. 27.

    et al. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell 140, 731–743 (2010)

  28. 28.

    et al. Infant colitis–it’s in the genes. Lancet 376, 1272 (2010)

  29. 29.

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

  30. 30.

    , , & Hck is a key regulator of gene expression in alternatively activated human monocytes. J. Biol. Chem. 286, 36709–36723 (2011)

Download references

Acknowledgements

We thank all the subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. UK case collections were supported by the National Association for Colitis and Crohn’s disease; Wellcome Trust grant 098051 (L.J., C.A.A., J.C.B.); Medical Research Council UK; the Catherine McEwan Foundation; an NHS Research Scotland career fellowship (R.K.R.); Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy’s & Saint Thomas’ National Health Service Trust, King’s College London, Addenbrooke’s Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The British 1958 Birth Cohort DNA collection was funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and the UK National Blood Service controls by the Wellcome Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium, which 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.). Additional funds were provided by funding to J.H.C. (DK062429-S1 and Crohn’s & Colitis Foundation of America, Senior Investigator Award (5-2229)) and R.H.D. (CA141743). K.Y.H. is supported by the National Institutes of Health (NIH) MSTP TG T32GM07205 training award. Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds, National Center for Research Resources (NCRR) grant M01-RR00425, UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) Grant (UL1 TR000124-01), the Southern California Diabetes and Endocrinology Research Grant (DERC) (DK063491), The Helmsley Foundation (D.P.M.) and the Crohn's and Colitis Foundation of America (D.P.M.). R.J.X. and A.N.A. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation. The Netherlands Organization for Scientific Research supported R.K.W. with a clinical fellowship grant (90.700.281) and C.W. (VICI grant 918.66.620). C.W. is also supported by the Celiac Disease Consortium (BSIK03009). This study was also supported by the German Ministry of Education and Research through the National Genome Research Network, the Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’ and DFG grant no. FR 2821/2-1. S.B. was supported by DFG BR 1912/6-1 and the Else Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). Italian case collections were supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition and funded by the Italian Ministry of Health GR-2008-1144485. Activities in Sweden were supported by the Swedish Society of Medicine, Ihre Foundation, Örebro University Hospital Research Foundation, Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, and the Swedish Medical Research Council. D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. We acknowledge a grant from Viborg Regional Hospital, Denmark. V. Andersen was supported by SHS Aabenraa, Denmark. We acknowledge funding provided by the Royal Brisbane and Women’s Hospital Foundation, National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). We acknowledge the following groups that provided biological samples or data for this study: the Inflammatory Bowel in South Eastern Norway (IBSEN) study group, the Norwegian Bone Marrow Donor Registry (NMBDR), the Avon Longitudinal Study of Parents and Children, the Human Biological Data Interchange and Diabetes UK, and Banco Nacional de ADN, Salamanca. This research also uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the NIDDK, National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation (JDRF) and supported by U01 DK062418. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.

Author information

Author notes

    • Luke Jostins
    • , Stephan Ripke
    • , Jeffrey C. Barrett
    •  & Judy H Cho

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

    • Luke Jostins
    • , Carl A. Anderson
    •  & Jeffrey C. Barrett
  2. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Stephan Ripke
    •  & Mark J. Daly
  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Stephan Ripke
    •  & Mark J. Daly
  4. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen 9700 RB, The Netherlands.

    • Rinse K. Weersma
    •  & Dirk De Jong
  5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

    • Richard H. Duerr
    • , Leonard Baidoo
    • , Karin Fransen
    •  & Miguel Regueiro
  6. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.

    • Richard H. Duerr
  7. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California 90048, USA.

    • Dermot P. McGovern
    • , Stephan R. Targan
    •  & Kent D. Taylor
  8. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

    • Dermot P. McGovern
    • , Talin Haritunians
    • , Jerome I. Rotter
    •  & Kent D. Taylor
  9. Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.

    • Ken Y. Hui
    •  & Judy H Cho
  10. Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.

    • James C. Lee
    •  & Miles Parkes
  11. Department of Health Studies, University of Chicago, Chicago, Illinois 60637, USA.

    • L. Philip Schumm
  12. Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut 06520, USA.

    • Yashoda Sharma
    • , Kaida Ning
    • , Clara Abraham
    • , Matija Hedl
    •  & Judy H Cho
  13. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Jonah Essers
  14. University of Maribor, Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Maribor 2000, Slovenia.

    • Mitja Mitrovic
    •  & Uros Potocnik
  15. University Medical Center Groningen, Department of Genetics, Groningen 9700 RB, The Netherlands.

    • Mitja Mitrovic
  16. Department of Clinical and Experimental Medicine, Gastroenterology section, KU Leuven, Leuven 3000, Belgium.

    • Isabelle Cleynen
    •  & Severine Vermeire
  17. Unit of Animal Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) and Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium.

    • Emilie Theatre
    •  & Michel Georges
  18. Division of Gastroenterology, Centre Hospitalier Universitaire, Université de Liège, Liège 4000, Belgium.

    • Emilie Theatre
    •  & Edouard Louis
  19. Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK.

    • Sarah L. Spain
    • , Natalie J. Prescott
    •  & Christopher G. Mathew
  20. Division of Rheumatology Immunology and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Soumya Raychaudhuri
    •  & Xinli Hu
  21. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Soumya Raychaudhuri
  22. Division of Genetics, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Soumya Raychaudhuri
  23. Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec H1T 1C8, Canada.

    • Philippe Goyette
    • , Gabrielle Boucher
    •  & John D. Rioux
  24. Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07102, USA.

    • Zhi Wei
  25. Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Jean-Paul Achkar
  26. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Jean-Paul Achkar
  27. Peninsula College of Medicine and Dentistry, Exeter EX1 2LU, UK.

    • Tariq Ahmad
  28. Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, 1070 Belgium.

    • Leila Amininejad
    •  & Denis Franchimont
  29. Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts 02114, USA.

    • Ashwin N. Ananthakrishnan
    • , Kathy L. Devaney
    •  & Ramnik J. Xavier
  30. Viborg Regional Hospital, Medical Department, Viborg 8800, Denmark.

    • Vibeke Andersen
  31. Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, and School of Medicine, University of Adelaide, Adelaide 5000, Australia.

    • Jane M. Andrews
  32. Institute of Clinical Chemistry, Christian-Albrechts-University, Kiel 24105, Germany.

    • Tobias Balschun
    • , David Ellinghaus
    • , Stefan Schreiber
    •  & Andre Franke
  33. Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide 5000, Australia.

    • Peter A. Bampton
  34. Division of Gastroenterology, McGill University Health Centre, Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada.

    • Alain Bitton
    •  & Jürgen Glas
  35. Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich 80336, Germany.

    • Stephan Brand
  36. Department of Gastroenterology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin 10117, Germany.

    • Carsten Büning
  37. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York City, New York 10029, USA.

    • Ariella Cohain
    • , Bin Zhang
    •  & Eric E. Schadt
  38. Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn 53012, Germany.

    • Sven Cichon
  39. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 14 183, Sweden.

    • Mauro D’Amato
  40. Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.

    • Marla Dubinsky
  41. Torbay Hospital, Department of Gastroenterology, Torbay, Devon TQ2 7AA, UK.

    • Cathryn Edwards
  42. School of Medical Sciences, Faculty of Medical & Health Sciences, The University of Auckland, Auckland 1142, New Zealand.

    • Lynnette R. Ferguson
    •  & Angharad R. Morgan
  43. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen T9700 RB, The Netherlands.

    • Karin Fransen
    •  & Cisca Wijmenga
  44. Department of Medicine, University of Otago, Christchurch 8140, New Zealand.

    • Richard Gearry
  45. Department of Gastroenterology, Christchurch Hospital, Christchurch 8011, New Zealand.

    • Richard Gearry
  46. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.

    • Christian Gieger
  47. St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK.

    • Ailsa Hart
  48. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham NG7 1AW, UK.

    • Chris Hawkey
  49. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo 0424, Norway.

    • Tom H. Karlsen
  50. Kaunas University of Medicine, Department of Gastroenterology, Kaunas 44307, Lithuania.

    • Limas Kupcinskas
    •  & Jurgita Sventoraityte
  51. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    • Subra Kugathasan
  52. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo 71013, Italy.

    • Anna Latiano
    • , Orazio Palmieri
    •  & Vito Annese
  53. Ghent University Hospital, Department of Gastroenterology and Hepatology, Ghent 9000, Belgium.

    • Debby Laukens
    •  & Martine De Vos
  54. School of Medicine and Pharmacology, The University of Western Australia, Fremantle, Western Australia 6009, Australia.

    • Ian C. Lawrance
  55. Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

    • Charlie W. Lees
    •  & Jack Satsangi
  56. Department of Gastroenterology, The Townsville Hospital, Townsville, Queensland 4810, Australia.

    • Gillian Mahy
  57. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.

    • John Mansfield
  58. Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

    • Craig Mowat
  59. Genetic Medicine, MAHSC, University of Manchester, Manchester M13 9PL, UK.

    • William Newman
  60. Academic Medical Center, Department of Gastroenterology, Amsterdam 1105 AZ, The Netherlands.

    • Cyriel Y. Ponsioen
  61. University of Maribor, Faculty for Chemistry and Chemical Engineering, Maribor 2000, Slovenia.

    • Uros Potocnik
  62. Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow G3 8SJ, UK.

    • Richard K. Russell
    •  & David C. Wilson
  63. Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Department of Gastroenterology, London SE1 7EH, UK.

    • Jeremy D. Sanderson
  64. Department of Gastroenterology, Hospital Clinic/Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

    • Miquel Sans
  65. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Barcelona 08036, Spain.

    • Miquel Sans
  66. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Kiel 24118, Germany.

    • Stefan Schreiber
    •  & Sebastian Zeissig
  67. Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane 4029, Australia.

    • Lisa A. Simms
    •  & Graham Radford-Smith
  68. Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.

    • Mark Tremelling
  69. Department of Gastroenterology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.

    • Hein W. Verspaget
  70. Child Life and Health, University of Edinburgh, Edinburgh, Scotland EH9 1UW, UK.

    • David C. Wilson
  71. Institute of Human Genetics and Department of Neurology, Technische Universität München, Munich 80336, Germany.

    • Juliane Winkelmann
  72. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Ramnik J. Xavier
  73. Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut 06520, USA.

    • Clarence K. Zhang
    •  & Hongyu Zhao
  74. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario M5G 1X5, Canada.

    • Mark S. Silverberg
  75. Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence 50134, Italy.

    • Vito Annese
  76. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  77. Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

    • Hakon Hakonarson
  78. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, and Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

    • Steven R. Brant
  79. Department of Gastroenterology, Royal Brisbane and Women’s Hospital, and School of Medicine, University of Queensland, Brisbane 4029, Australia.

    • Graham Radford-Smith
  80. Department of Gastroenterology, University Hospital Leuven, Leuven 3000, Belgium

    • Severine Vermeire

Consortia

  1. The International IBD Genetics Consortium (IIBDGC)

    Lists of participants and their affiliations appear in the Supplementary Information.

Authors

  1. Search for Luke Jostins in:

  2. Search for Stephan Ripke in:

  3. Search for Rinse K. Weersma in:

  4. Search for Richard H. Duerr in:

  5. Search for Dermot P. McGovern in:

  6. Search for Ken Y. Hui in:

  7. Search for James C. Lee in:

  8. Search for L. Philip Schumm in:

  9. Search for Yashoda Sharma in:

  10. Search for Carl A. Anderson in:

  11. Search for Jonah Essers in:

  12. Search for Mitja Mitrovic in:

  13. Search for Kaida Ning in:

  14. Search for Isabelle Cleynen in:

  15. Search for Emilie Theatre in:

  16. Search for Sarah L. Spain in:

  17. Search for Soumya Raychaudhuri in:

  18. Search for Philippe Goyette in:

  19. Search for Zhi Wei in:

  20. Search for Clara Abraham in:

  21. Search for Jean-Paul Achkar in:

  22. Search for Tariq Ahmad in:

  23. Search for Leila Amininejad in:

  24. Search for Ashwin N. Ananthakrishnan in:

  25. Search for Vibeke Andersen in:

  26. Search for Jane M. Andrews in:

  27. Search for Leonard Baidoo in:

  28. Search for Tobias Balschun in:

  29. Search for Peter A. Bampton in:

  30. Search for Alain Bitton in:

  31. Search for Gabrielle Boucher in:

  32. Search for Stephan Brand in:

  33. Search for Carsten Büning in:

  34. Search for Ariella Cohain in:

  35. Search for Sven Cichon in:

  36. Search for Mauro D’Amato in:

  37. Search for Dirk De Jong in:

  38. Search for Kathy L. Devaney in:

  39. Search for Marla Dubinsky in:

  40. Search for Cathryn Edwards in:

  41. Search for David Ellinghaus in:

  42. Search for Lynnette R. Ferguson in:

  43. Search for Denis Franchimont in:

  44. Search for Karin Fransen in:

  45. Search for Richard Gearry in:

  46. Search for Michel Georges in:

  47. Search for Christian Gieger in:

  48. Search for Jürgen Glas in:

  49. Search for Talin Haritunians in:

  50. Search for Ailsa Hart in:

  51. Search for Chris Hawkey in:

  52. Search for Matija Hedl in:

  53. Search for Xinli Hu in:

  54. Search for Tom H. Karlsen in:

  55. Search for Limas Kupcinskas in:

  56. Search for Subra Kugathasan in:

  57. Search for Anna Latiano in:

  58. Search for Debby Laukens in:

  59. Search for Ian C. Lawrance in:

  60. Search for Charlie W. Lees in:

  61. Search for Edouard Louis in:

  62. Search for Gillian Mahy in:

  63. Search for John Mansfield in:

  64. Search for Angharad R. Morgan in:

  65. Search for Craig Mowat in:

  66. Search for William Newman in:

  67. Search for Orazio Palmieri in:

  68. Search for Cyriel Y. Ponsioen in:

  69. Search for Uros Potocnik in:

  70. Search for Natalie J. Prescott in:

  71. Search for Miguel Regueiro in:

  72. Search for Jerome I. Rotter in:

  73. Search for Richard K. Russell in:

  74. Search for Jeremy D. Sanderson in:

  75. Search for Miquel Sans in:

  76. Search for Jack Satsangi in:

  77. Search for Stefan Schreiber in:

  78. Search for Lisa A. Simms in:

  79. Search for Jurgita Sventoraityte in:

  80. Search for Stephan R. Targan in:

  81. Search for Kent D. Taylor in:

  82. Search for Mark Tremelling in:

  83. Search for Hein W. Verspaget in:

  84. Search for Martine De Vos in:

  85. Search for Cisca Wijmenga in:

  86. Search for David C. Wilson in:

  87. Search for Juliane Winkelmann in:

  88. Search for Ramnik J. Xavier in:

  89. Search for Sebastian Zeissig in:

  90. Search for Bin Zhang in:

  91. Search for Clarence K. Zhang in:

  92. Search for Hongyu Zhao in:

  93. Search for Mark S. Silverberg in:

  94. Search for Vito Annese in:

  95. Search for Hakon Hakonarson in:

  96. Search for Steven R. Brant in:

  97. Search for Graham Radford-Smith in:

  98. Search for Christopher G. Mathew in:

  99. Search for John D. Rioux in:

  100. Search for Eric E. Schadt in:

  101. Search for Mark J. Daly in:

  102. Search for Andre Franke in:

  103. Search for Miles Parkes in:

  104. Search for Severine Vermeire in:

  105. Search for Jeffrey C. Barrett in:

  106. Search for Judy H Cho in:

Contributions

R.K.W., R.H.D., D.P.M., C.G.M., J.D.R., E.E.S., M.J.D., A.F., M.P. and S.V. contributed equally to the manuscript. J.H.C., J.C.B., R.K.W., R.H.D., D.P.M., A.F., M.P., C.G.M., J.D.R., S.V., M.D.A. and V. Annese conceived, designed and managed the study and managed the funding. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., R.H.D., D.P.M., M.J.D., M.P. and C.G.M. were involved in manuscript preparation. J.H.C., J.C.B., L.J., S. Ripke, R.K.W., K.Y.H., C.A.A., J.E., K.N., S.L.S., S. Raychaudhuri, Z.W., C.A., A.C., G.B., M.H., X.H., B.Z., C.K.Z., H.Z., J.D.R., E.E.S. and M.J.D. performed or supervised statistical and computational analyses. R.K.W., R.H.D., D.P.M., J.C.L., L.P.S., Y.S., P.G., J.-P.A., T.A., L.A., A.N.A., V. Andersen, J.M.A., L.B., P.A.B., A.B., S.B., C.B., S.C., M.D.A., D.D.J., K.L.D., M.D., C.E., L.R.F., D.F., M.G., C.G., R.G., J.G., A.H., C.H., T.H.K., L.K., S.K., A.L., D.L., E.L., I.C.L., C.W.L., A.R.M., C.M., G.M., J.M., W.N., O.P., C.Y.P., U.P., N.J.P., M.R., J.I.R., R.K.R., J.D.S., M.S., J. Satsangi, S.S., L.A.S., J. Sventoraityte, S.R.T., M.T., H.W.V., M.D.V., C.W., D.C.W., J.W., R.J.X., S.Z., M.S.S., V. Annese, H.H., IIBDGC, S.R.B., J.D.R., G.R.S., C.G.M., A.F., M.P., S.V. and J.H.C. were involved in study subject recruitment and assembling phenotypic data. R.K.W., R.H.D., D.P.M., L.P.S., Y.S., M.M., I.C., E.T., T.B., D.E., K.F., T.H., K.D.T., C.G.M., A.F., M.P. and J.H.C. established DNA collections, genotyping and data management. All authors read and approved the final manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Judy H Cho.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Text, Supplementary Figures 1-12, full legends for Supplementary Tables 1-6, Supplementary References and a list of IBD Genetics Consortium members – see Supplementary Contents for details.

Zip files

  1. 1.

    Supplementary Tables

    This zipped files contains Supplementary Tables 1-6 as follows: 1 shows the GWAS and Immunochip samples used in the study; 2 contains complete details of 163 IBD loci; 3 contains details of disease overlaps with IMD, PID and MSMD described in section 2 of the methods; 4 contains detailed enrichment statistics for all GO terms and canonical pathways; 5 contains the signals of selection at IBD loci; 6 shows enrichment scores for genes in IBD loci within co-expression modules. Supplementary Table 2, which is contained in this zipped file, has been replaced, as there was an error in the original file. In the ‘Detailed assoc stats’ tab, the ‘IC risk’ and ‘IC_nonrisk’ column labels were inadvertently switched. In addition, clarification of the cohort used to determine the odds ratio (OR) shown in the ‘Detailed assoc stats’ and ‘Main Table’ tabs has been included. This file was replaced online on 31 January 2013.

  2. 2.

    Supplementary Data

    This zipped file is a Cytoscape file for the macrophage enriched, omental adipose Bayesian network.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature11582

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.