title: Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.
abstract: 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.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Ploen, Germany.
authors.forename: Tobias L
authors.initials: TL
authors.lastname: Lenz
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.
authors.forename: Aaron J
authors.identifier: http://orcid.org/0000-0001-6750-5335
authors.initials: AJ
authors.lastname: Deutsch
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.|National 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Eyre
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Abecasis
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.|Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dafna D
authors.identifier: http://orcid.org/0000-0002-9074-0592
authors.initials: DD
authors.lastname: Gladman
authors.affiliation: Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Gockel
authors.affiliation: Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.|Department of Rheumatology, Umeå University, Umeå, Sweden.
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.|Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lam C
authors.initials: LC
authors.lastname: Tsoi
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: David A
authors.identifier: http://orcid.org/0000-0002-0637-2265
authors.initials: DA
authors.lastname: van Heel
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.|National 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.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
authors.forename: Mira M
authors.identifier: http://orcid.org/0000-0002-3438-1919
authors.initials: MM
authors.lastname: Wouters
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.identifier: http://orcid.org/0000-0002-5635-1614
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Paul I W
authors.identifier: http://orcid.org/0000-0001-7735-7858
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.|Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.|Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015236:HLA-C Antigens / Q000235:genetics*; D006681:HLA-D Antigens / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D015236:HLA-C Antigens; C491620:HLA-C*06:02 antigen; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I