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High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Nature Genetics volume 47, pages 172–179 (2015)Cite this article

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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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Figure 1: Primary univariate association analyses of Crohn's disease and ulcerative colitis.
Figure 2: Variance explained by four-digit HLA alleles in Crohn's disease and ulcerative colitis.
Figure 3: Correlated association signals at HLA alleles support potential alternate association models for both Crohn's disease and ulcerative colitis.
Figure 4: HLA-DR peptide-binding groove electrostatic properties and risk of IBD.
Figure 5: Non-additive effect models in Crohn's disease and ulcerative colitis.
Figure 6: Comparison of OR values in Crohn's disease and ulcerative colitis for HLA alleles identified from HLA-focused models.

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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

  1. Philippe Goyette, Gabrielle Boucher and Hu Zhang: These authors contributed equally to this work.

  2. Hu Zhang, Tom H Karlsen, Andre Franke and John D Rioux: These authors jointly supervised this work

Authors and Affiliations

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

    Philippe Goyette, Gabrielle Boucher, Gabrielle Boucher, Philippe Goyette, John D Rioux & 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 & Andre Franke

  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK

    Luke Jostins & Luke Jostins

  6. Christ Church, University of Oxford, St Aldates, UK

    Luke Jostins & Luke Jostins

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

    Hailiang Huang, Stephan Ripke, Mark J Daly, 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, Hailiang Huang, Stephan Ripke, Ramnik J Xavier & Mark J Daly

  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, Vito Annese, Anna Latiano & Orazio Palmieri

  12. Unit of Gastroenterology SOD2 (Strutture Organizzative Dipartimentali), Azienda Ospedaliero Universitaria (AOU) Careggi, Florence, Italy

    Vito Annese & 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, Department of Medicine, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Leonard Baidoo, Richard H Duerr, Miguel Regueiro, Regan Scott & Richard H Duerr

  17. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA

    Richard H Duerr & Richard H Duerr

  18. Wellcome Trust Sanger Institute, Hinxton, UK

    Carl A Anderson, Jeffrey C Barrett, Jimmy Z Liu & Jeffrey C Barrett

  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 & Dermot P B McGovern

  20. Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA

    L Philip Schumm & 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. Department of Transplantation Medicine, Division of Cancer, Research Institute of Internal Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway

    Tom H Karlsen & Tom H Karlsen

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

    Tom H Karlsen & Tom H Karlsen

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

    Tom H Karlsen & Tom H Karlsen

  28. Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada

    Guy Aumais, John D Rioux & John D Rioux

  29. Department of Internal Medicine, Section of Digestive Diseases, 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. Department of Gastroenterology and Hepatology, Inflammatory Bowel Disease Service, 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. Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, 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. Department of Gastroenterology, IBD Center, 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

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  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

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  83. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK

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  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

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  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

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  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

    Zhi Wei, Zhi Wei, 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

Authors
  1. Philippe Goyette
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  2. Gabrielle Boucher
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  3. Dermot Mallon
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  4. Eva Ellinghaus
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  5. Luke Jostins
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  6. Hailiang Huang
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  7. Stephan Ripke
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  8. Elena S Gusareva
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  9. Vito Annese
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  10. Stephen L Hauser
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  11. Jorge R Oksenberg
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  12. Ingo Thomsen
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  13. Stephen Leslie
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  14. Mark J Daly
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  15. Kristel Van Steen
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  16. Richard H Duerr
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  18. Dermot P B McGovern
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  19. L Philip Schumm
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  20. James A Traherne
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  21. Mary N Carrington
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  22. Vasilis Kosmoliaptsis
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  23. Tom H Karlsen
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  24. Andre Franke
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  25. John D Rioux
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Consortia

International Inflammatory Bowel Disease Genetics Consortium

  • Clara Abraham
  • , Jean-Paul Achkar
  • , Tariq Ahmad
  • , Leila Amininejad
  • , Ashwin N Ananthakrishnan
  • , Vibeke Andersen
  • , Carl A Anderson
  • , Jane M Andrews
  • , Vito Annese
  • , Guy Aumais
  • , Leonard Baidoo
  • , Robert N Baldassano
  • , Tobias Balschun
  • , Peter A Bampton
  • , Murray Barclay
  • , Jeffrey C Barrett
  • , Theodore M Bayless
  • , Johannes Bethge
  • , Joshua C Bis
  • , Alain Bitton
  • , Gabrielle Boucher
  • , Stephan Brand
  • , Steven R Brant
  • , Carsten Büning
  • , Angela Chew
  • , Judy H Cho
  • , Isabelle Cleynen
  • , Ariella Cohain
  • , Anthony Croft
  • , Mark J Daly
  • , Mauro D′Amato
  • , Silvio Danese
  • , Dirk De Jong
  • , Martine De Vos
  • , Goda Denapiene
  • , Lee A Denson
  • , Kathy L Devaney
  • , Olivier Dewit
  • , Renata D′Inca
  • , Marla Dubinsky
  • , Richard H Duerr
  • , Cathryn Edwards
  • , David Ellinghaus
  • , Jonah Essers
  • , Lynnette R Ferguson
  • , Eleonora A Festen
  • , Philip Fleshner
  • , Tim Florin
  • , Denis Franchimont
  • , Andre Franke
  • , Karin Fransen
  • , Richard Gearry
  • , Michel Georges
  • , Christian Gieger
  • , Jürgen Glas
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  • , Todd Green
  • , Anne M Griffiths
  • , Stephen L Guthery
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  • , Katherine Hanigan
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  • , John D Rioux
  • , Stephan Ripke
  • , Rebecca Roberts
  • , Richard K Russell
  • , Jeremy D Sanderson
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  • , Jack Satsangi
  • , Eric E Schadt
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  • , Regan Scott
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  • , Mark S Silverberg
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  • , Jurgita Skieceviciene
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  • , A Hillary Steinhart
  • , Joanne M Stempak
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  • , Jurgita Sventoraityte
  • , Stephan R Targan
  • , Kirstin M Taylor
  • , Anje ter Velde
  • , Emilie Theatre
  • , Leif Torkvist
  • , Mark Tremelling
  • , Andrea van der Meulen
  • , Suzanne van Sommeren
  • , Eric Vasiliauskas
  • , Severine Vermeire
  • , Hein W Verspaget
  • , Thomas Walters
  • , Kai Wang
  • , Ming-Hsi Wang
  • , Rinse K Weersma
  • , Zhi Wei
  • , David Whiteman
  • , Cisca Wijmenga
  • , David C Wilson
  • , Juliane Winkelmann
  • , Ramnik J Xavier
  • , Sebastian Zeissig
  • , Bin Zhang
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  • , Hu Zhang
  • , Wei Zhang
  • , Hongyu Zhao
  • , Zhen Z Zhao
  • , Australia and New Zealand IBDGC
  • , Belgium IBD Genetics Consortium
  • , Italian Group for IBD Genetic Consortium
  • , NIDDK Inflammatory Bowel Disease Genetics Consortium
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  • , Wellcome Trust Case Control Consortium
  •  & Quebec IBD Genetics Consortium

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.

Corresponding author

Correspondence to John D Rioux.

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Competing interests

The authors declare no competing financial interests.

Additional information

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

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

A list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Tables 1, 5–7 and 10, and Supplementary Note. (PDF 11043 kb)

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. (XLSX 68 kb)

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. (XLSX 174 kb)

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. (XLSX 281 kb)

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). (XLSX 21 kb)

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). (XLSX 16 kb)

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). (XLSX 23 kb)

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. (XLSX 1228 kb)

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. (XLSX 76 kb)

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Goyette, P., Boucher, G., Mallon, D. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet 47, 172–179 (2015). https://doi.org/10.1038/ng.3176

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