Abstract

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules1. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles2,3. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

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Acknowledgements

We would like to thank the International PSC study group (http://www.ipscsg.org/) for sharing data. We are grateful to B.A. Lie and K. Holm for helpful discussions. J.D.R. holds a Canada Research Chair, and this work was supported by a US National Institute of Diabetes and Digestive and Kidney Diseases grant (NIDDK; R01 DK064869 and U01 DK062432). The laboratory of A.F. is supported by the German Ministry of Education and Research (BMBF) grant program e:Med (sysINFLAME). A.F. receives infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces' and holds an endowment professorship (Peter Hans Hofschneider Professorship) of the Foundation for Experimental Biomedicine (Zurich, Switzerland). Grant support for T.H.K. and A.F. was received from the European Union Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). M.N.C. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), Frederick National Laboratory, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. J.C.B. was supported by a Wellcome Trust grant (WT098051). D.M. and V.K. are supported by the NIHR Cambridge Biomedical Research Centre. L.P.S. is supported by an NIDDK grant (U01 DK062429-14). J.A.T. is supported by the UK Medical Research Council. D.P.B.M. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, the European Union (305479) and by grants from the NIDDK (U01 DK062413, P01 DK046763-19, U54 DE023789-01), the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI067068) and the Agency for Healthcare Research and Quality (AHRQ; HS021747). R.H.D. holds the Inflammatory Bowel Disease Genetic Research endowed chair at the University of Pittsburgh and was supported by an NIDDK grant (U01 DK062420) and a US National Cancer Institute grant (CA141743). S.L.H. and J.R.O. would like to also acknowledge the support of the US NIH (R01 NS049477 and 1U19 A1067152) and the National Multiple Sclerosis Society (RG 2899-D11). S.L. wishes to acknowledge support from the Australian National Health and Medical Research Council (R.D. Wright Career Development Fellowship, APP1053756).

Author information

Author notes

    • Philippe Goyette
    •  & Gabrielle Boucher

    These authors contributed equally to this work.

    • Tom H Karlsen
    • , Andre Franke
    •  & John D Rioux

    These authors jointly supervised this work

Affiliations

  1. Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.

    • Philippe Goyette
    • , Gabrielle Boucher
    •  & John D Rioux
  2. Department of Surgery, University of Cambridge, Cambridge, UK.

    • Dermot Mallon
    •  & Vasilis Kosmoliaptsis
  3. National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.

    • Dermot Mallon
    •  & Vasilis Kosmoliaptsis
  4. Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany.

    • Eva Ellinghaus
    • , Ingo Thomsen
    • , Tobias Balschun
    • , David Ellinghaus
    • , Andre Franke
    •  & Stefan Schreiber
  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

    • Luke Jostins
  6. Christ Church, University of Oxford, St Aldates, UK.

    • Luke Jostins
  7. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Hailiang Huang
    • , Stephan Ripke
    •  & Mark J Daly
  8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Hailiang Huang
    • , Stephan Ripke
    • , Mark J Daly
    • , Todd Green
    •  & Ramnik J Xavier
  9. Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium.

    • Elena S Gusareva
    •  & Kristel Van Steen
  10. Bioinformatics and Modeling, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.

    • Elena S Gusareva
    •  & Kristel Van Steen
  11. Unit of Gastroenterology, IRCCS-CSS (Istituto di Ricovero e Cura a Carattere Scientifico–Casa Sollievo della Sofferenza) Hospital, San Giovanni Rotondo, Italy.

    • Vito Annese
    • , Anna Latiano
    •  & Orazio Palmieri
  12. Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy.

    • Vito Annese
  13. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

    • Stephen L Hauser
    •  & Jorge R Oksenberg
  14. Murdoch Children's Research Institute, Parkville, Victoria, Australia.

    • Stephen Leslie
  15. Department of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.

    • Stephen Leslie
  16. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Leonard Baidoo
    • , Richard H Duerr
    • , Miguel Regueiro
    •  & Regan Scott
  17. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  18. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Carl A Anderson
    • , Jeffrey C Barrett
    •  & Jimmy Z Liu
  19. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Philip Fleshner
    • , Talin Haritunians
    • , Andrew Ippoliti
    • , Dermot P B McGovern
    • , Stephan R Targan
    •  & Eric Vasiliauskas
  20. Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

    • L Philip Schumm
  21. Cambridge Institute for Medical Research, Cambridge, UK.

    • James A Traherne
  22. Department of Pathology, University of Cambridge, Cambridge, UK.

    • James A Traherne
  23. Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.

    • Mary N Carrington
  24. Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA.

    • Mary N Carrington
  25. Research Institute of Internal Medicine, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.

    • Tom H Karlsen
  26. Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.

    • Tom H Karlsen
  27. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Tom H Karlsen
  28. Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.

    • Guy Aumais
    •  & John D Rioux
  29. Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

    • Clara Abraham
    • , Matija Hedl
    • , Sok Meng Evelyn Ng
    • , Kaida Ning
    • , Ioannis Oikonomou
    • , Deborah D Proctor
    • , Yashoda Sharma
    •  & Wei Zhang
  30. Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jean-Paul Achkar
    • , Florian Rieder
    •  & Ming-Hsi Wang
  31. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jean-Paul Achkar
  32. Peninsula College of Medicine and Dentistry, Exeter, UK.

    • Tariq Ahmad
  33. Department of Gastroenterology, Erasmus Hospital, Brussels, Belgium.

    • Leila Amininejad
    •  & Denis Franchimont
  34. Department of Gastroenterology, Free University of Brussels, Brussels, Belgium.

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

    • Ashwin N Ananthakrishnan
    • , Kathy L Devaney
    • , Aylwin Ng
    •  & Ramnik J Xavier
  36. Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Ashwin N Ananthakrishnan
  37. Medical Department, Viborg Regional Hospital, Viborg, Denmark.

    • Vibeke Andersen
  38. Organ Center, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark.

    • Vibeke Andersen
  39. Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

    • Jane M Andrews
  40. Department of Gastroenterology, Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada.

    • Guy Aumais
  41. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Robert N Baldassano
    • , Hakon Hakonarson
    • , Marcin Imielinski
    •  & Kai Wang
  42. Department of Gastroenterology and Hepatology, Flinders Medical Centre and School of Medicine, Flinders University, Adelaide, South Australia, Australia.

    • Peter A Bampton
  43. Department of Medicine, University of Otago, Christchurch, New Zealand.

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

    • Theodore M Bayless
    • , Steven R Brant
    •  & Ming-Hsi Wang
  45. Department for General Internal Medicine, Christian Albrechts University, Kiel, Germany.

    • Johannes Bethge
    • , Susanna Nikolaus
    • , Stefan Schreiber
    •  & Sebastian Zeissig
  46. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
  47. Division of Gastroenterology, Royal Victoria Hospital, Montreal, Quebec, Canada.

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

    • Stephan Brand
  49. Department of Gastroenterology, Campus Charité Mitte, Universitatsmedizin Berlin, Berlin, Germany.

    • Carsten Büning
  50. IBD Unit, Fremantle Hospital, Fremantle, Western Australia, Australia.

    • Angela Chew
  51. School of Medicine and Pharmacology, University of Western Australia, Fremantle, Western Australia, Australia.

    • Angela Chew
    •  & Ian C Lawrance
  52. Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.

    • Judy H Cho
    •  & Ken Y Hui
  53. Department of Clinical and Experimental Medicine, Translational Research in Gastrointestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven, Belgium.

    • Isabelle Cleynen
    •  & Severine Vermeire
  54. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Ariella Cohain
    • , Eric E Schadt
    •  & Bin Zhang
  55. Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Anthony Croft
    • , Katherine Hanigan
    • , Graham Radford-Smith
    •  & Lisa A Simms
  56. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Mauro D′Amato
  57. IBD Center, Department of Gastroenterology, Istituto Clinico Humanitas, Milan, Italy.

    • Silvio Danese
  58. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

    • Dirk De Jong
  59. Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium.

    • Martine De Vos
    •  & Debby Laukens
  60. Center of Hepatology, Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania.

    • Goda Denapiene
  61. Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Lee A Denson
  62. Department of Gastroenterology, Université Catholique de Louvain (UCL) Cliniques Universitaires Saint-Luc, Brussels, Belgium.

    • Olivier Dewit
  63. Division of Gastroenterology, University Hospital Padua, Padua, Italy.

    • Renata D′Inca
  64. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marla Dubinsky
  65. Department of Gastroenterology, Torbay Hospital, Torbay, UK.

    • Cathryn Edwards
  66. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jonah Essers
    •  & Todd Green
  67. Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Jonah Essers
  68. Faculty of Medical and Health Sciences, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.

    • Lynnette R Ferguson
  69. Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.

    • Eleonora A Festen
    • , Suzanne van Sommeren
    •  & Rinse K Weersma
  70. Department of Gastroenterology, Mater Health Services, Brisbane, Queensland, Australia.

    • Tim Florin
  71. Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.

    • Karin Fransen
    • , Mitja Mitrovic
    •  & Cisca Wijmenga
  72. Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.

    • Richard Gearry
  73. Unit of Animal Genomics, GIGA-R (Groupe Interdisciplinaire de Génoprotéomique Appliquée) Research Center, University of Liege, Liege, Belgium.

    • Michel Georges
    •  & Emilie Theatre
  74. Faculty of Veterinary Medicine, University of Liege, Liege, Belgium.

    • Michel Georges
    •  & Emilie Theatre
  75. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
  76. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Anne M Griffiths
    • , Johan Van Limbergen
    •  & Thomas Walters
  77. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Stephen L Guthery
  78. Department of Medicine, Örebro University Hospital, Örebro, Sweden.

    • Jonas Halfvarson
  79. School of Health and Medical Sciences, Örebro University, Örebro, Sweden.

    • Jonas Halfvarson
  80. Department of Medicine, St Mark's Hospital, Harrow, UK.

    • Ailsa Hart
  81. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.

    • Chris Hawkey
  82. Molecular Epidemiology, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Nicholas K Hayward
    • , Grant W Montgomery
    • , David Whiteman
    •  & Zhen Z Zhao
  83. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.

    • Paul Henderson
    • , Richard K Russell
    •  & David C Wilson
  84. Child Life and Health, University of Edinburgh, Edinburgh, UK.

    • Paul Henderson
    •  & David C Wilson
  85. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Xinli Hu
    •  & Soumya Raychaudhuri
  86. Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.

    • Laimas Jonaitis
    • , Gediminas Kiudelis
    •  & Jurgita Skieceviciene
  87. Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.

    • Nicholas A Kennedy
    • , Charlie W Lees
    •  & Jack Satsangi
  88. Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.

    • Mohammed Azam Khan
    •  & William Newman
  89. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.

    • Mohammed Azam Khan
    •  & William Newman
  90. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Subra Kugathasan
  91. Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania.

    • Limas Kupcinskas
    •  & Jurgita Sventoraityte
  92. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
    • , Dunecan Massey
    •  & Miles Parkes
  93. Faculty of Medicine, University of Latvia, Riga, Latvia.

    • Marcis Leja
  94. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), Università di Firenze Strutture Organizzative Dipartimentali (SOD) Gastroenterologia e Nutrizione Ospedale Pediatrico Meyer, Florence, Italy.

    • Paolo Lionetti
  95. Division of Gastroenterology, Centre Hospitalier Universitaire (CHU) de Liège, Liege, Belgium.

    • Edouard Louis
  96. Department of Gastroenterology, Townsville Hospital, Townsville, Queensland, Australia.

    • Gillian Mahy
  97. Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, UK.

    • John Mansfield
  98. Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Natalie J Prescott
  99. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Christopher G Mathew
    • , Natalie J Prescott
    •  & Sarah L Spain
  100. Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Raquel Milgrom
    • , Mark S Silverberg
    • , A Hillary Steinhart
    •  & Joanne M Stempak
  101. Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Maribor, Slovenia.

    • Mitja Mitrovic
    •  & Urõs Potocnik
  102. Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.

    • Craig Mowat
    •  & Anne Phillips
  103. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Aylwin Ng
  104. Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong.

    • Siew C Ng
  105. Department of Genomics, Life & Brain Center, University Hospital Bonn, Bonn, Germany.

    • Markus Nöthen
  106. Department of Gastroenterology, Academic Medical Center, Amsterdam, the Netherlands.

    • Cyriel Y Ponsioen
    •  & Anje ter Velde
  107. Faculty for Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.

    • Urõs Potocnik
  108. Department of Gastroenterology, Royal Brisbane and Womens Hospital, Brisbane, Queensland, Australia.

    • Graham Radford-Smith
  109. Department of Gastroenterology, Université Catholique de Louvain (UCL), Centre Hospitalier Universitaire (CHU) Mont-Godinne, Mont-Godinne, Belgium.

    • Jean-Francois Rahier
  110. Department of Gastroenterology, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, St Thomas' Hospital, London, UK.

    • Jeremy D Sanderson
    •  & Kirstin M Taylor
  111. Department of Digestive Diseases, Hospital Quirón Teknon, Barcelona, Spain.

    • Miquel Sans
  112. Human Genetics, Genome Institute of Singapore, Singapore.

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

    • Mark Seielstad
  114. Department of Biology of Radiations and Human Health, Agenzia Nazionale per le Nuove Tecnologie l′Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.

    • Laura Stronati
  115. Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

    • Leif Torkvist
  116. Gastroenterology and General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.

    • Mark Tremelling
  117. Department of Gastroenterology, Leiden University Medical Center, Leiden, the Netherlands.

    • Andrea van der Meulen
    •  & Hein W Verspaget
  118. Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Severine Vermeire
  119. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Thomas Walters
  120. Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, USA.

    • Zhi Wei
  121. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
  122. Department of Neurology, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
  123. Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut, USA.

    • Clarence K Zhang
    •  & Hongyu Zhao
  124. Department of Gastroenterology, West China Hospital, Chengdu, China.

    • Hu Zhang
  125. State Key Laboratory of Biotherapy, Sichuan University West China University of Medical Sciences (WCUMS), Chengdu, China.

    • Hu Zhang

Consortia

  1. International Inflammatory Bowel Disease Genetics Consortium

    A full list of members and affiliations appears at the end of the paper.

    Australia and New Zealand IBDGC

    Belgium IBD Genetics Consortium

    Italian Group for IBD Genetic Consortium

    NIDDK Inflammatory Bowel Disease Genetics Consortium

    United Kingdom IBDGC

    Wellcome Trust Case Control Consortium

    Quebec IBD Genetics Consortium

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Contributions

J.D.R., M.J.D., K.V.S., V.K., T.H.K. and A.F. jointly supervised research. J.D.R., P.G., G.B., R.H.D., J.C.B., D.P.B.M., J.A.T., M.N.C., V.K. and A.F. conceived and designed the experiments. P.G., G.B., D.M. and L.J. performed statistical analysis. P.G., G.B., L.J. and E.S.G. analyzed the data. V.A., S.L.H., J.R.O., I.T., S.L. and L.P.S. contributed reagents, materials or analysis tools. P.G., G.B., E.E., H.H. and S.R. performed data quality control and imputation. J.D.R., P.G., G.B., D.M., D.P.B.M., V.K., T.H.K. and A.F. wrote the manuscript. All authors read and approved the final manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John D Rioux.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–13, Supplementary Tables 1, 5–7 and 10, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 2: Detailed primary and conditional association analyses of study-wide significant HLA alleles in CD.

    All HLA alleles showing study-wide significant association in CD (P < 5 × 10−6), the GWAS index SNP and a few additional alleles reaching significance in conditional analyses are presented. For these variants, association statistics are shown for both the primary analysis and conditional analyses on different models. Finally, this table presents pairwise conditional analyses.

  2. 2.

    Supplementary Table 3: Detailed primary and conditional association analyses of study-wide significant HLA alleles in UC.

    All HLA alleles showing study-wide significant association in UC (P < 5 × 10−6), the GWAS index SNP and a few additional alleles reaching significance in conditional analyses are presented. For these variants, association statistics are shown for both the primary analysis and conditional analyses on different models. Finally, this table presents pairwise conditional analyses.

  3. 3.

    Supplementary Table 4: Primary univariate analysis of single–amino acid variants and omnibus association tests at amino acid positions for all HLA genes in CD and UC.

    This table includes detailed association results for amino acid variants, including per-position (omnibus) analyses (Supplementary Fig. 4). See the Online Methods and Supplementary Figure 5 for interpretation of the per-position results.

  4. 4.

    Supplementary Table 8: Comparison of additive and non-additive models.

    Results for the additive, recessive, dominant and general effect models (additive and dominance terms) are shown for all HLA alleles identified as independent signals in our analyses (Fig. 3).

  5. 5.

    Supplementary Table 10: Non-additive effect for UC in HLA-DRB1.

    Non-additive effect for UC in HLA-DRB1, presented for every possible pair of common alleles (>5%). Association analysis was conducted in the subset of samples carrying the specific alleles as homozygotes or heterozygotes (Online Methods).

  6. 6.

    Supplementary Table 11: Benchmarking of HLA allele imputation.

    This table includes per-allele accuracy estimates for imputed alleles in Italian and Norwegian samples (Online Methods and Supplementary Table 10).

  7. 7.

    Supplementary Table 12: Primary univariate association results for SNP variants.

    Primary univariate association results for SNPs (genotyped and imputed), with minor allele frequency greater than 0.5% and imputation quality info score greater than 0.5.

  8. 8.

    Supplementary Table 13: Primary univariate association results for all classical HLA alleles in CD and UC.

    This table includes detailed primary association results for every HLA allele included in this study, for both CD and UC.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3176

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