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Nat Genet. 2015 Sep;47(9):1085-90. doi: 10.1038/ng.3379. Epub 2015 Aug 10.

Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

Author information

  • 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 2Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
  • 3Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Ploen, Germany.
  • 4Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 5Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
  • 6Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
  • 7Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.
  • 8Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
  • 9Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 10Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 11Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
  • 12National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
  • 13Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
  • 14Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
  • 15Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
  • 16Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • 17Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
  • 18Institute of Human Genetics, University of Bonn, Bonn, Germany.
  • 19Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
  • 20Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
  • 21Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
  • 22Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
  • 23Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 24Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
  • 25Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
  • 26Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
  • 27Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
  • 28Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 29Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
  • 30Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
  • 31Department of Rheumatology, Umeå University, Umeå, Sweden.
  • 32Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 33Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
  • 34Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
  • 35Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
  • 36Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 37Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.


Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.

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