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.

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Acknowledgements

This project was supported by grants from the German Research Foundation (DFG; LE 2593/1-1 and LE 2593/2-1 (T.L.L.), GO 1795/1-1 (I.G.), KN 378/2-1 (M.K.) and SCHU 1596/5-1 (J.S.)), by grants from the US National Institutes of Health (1R01AR062886 (P.I.W.d.B.), R01AR065183 (J.T.E.), 1R01AR063759-01A1 (S.R.), 5U01GM092691 (S.R.) and 1UH2AR067677-01 (S.R.)), by the IMI (European Union)–funded program BTCure (L.K.) and by the Netherlands Organization for Scientific Research (Vernieuwingsimpuls VIDI Award NWO project 016.126.354 (P.I.W.d.B.)). Sample collection for J.M. was supported by a grant from the Instituto de Salud Carlos III (RD12/0009). M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the DFG-funded Excellence Cluster ImmunoSensation.

Author information

Author notes

    • Tobias L Lenz
    •  & Aaron J Deutsch

    These authors contributed equally to this work.

Affiliations

  1. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Tobias L Lenz
    • , Aaron J Deutsch
    • , Buhm Han
    • , Xinli Hu
    • , Yukinori Okada
    • , Shamil R Sunyaev
    •  & Soumya Raychaudhuri
  2. Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Tobias L Lenz
    • , Aaron J Deutsch
    • , Buhm Han
    • , Xinli Hu
    • , Yukinori Okada
    • , Shamil R Sunyaev
    •  & Soumya Raychaudhuri
  3. Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Ploen, Germany.

    • Tobias L Lenz
  4. Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Aaron J Deutsch
    • , Buhm Han
    • , Xinli Hu
    • , Yukinori Okada
    •  & Soumya Raychaudhuri
  5. Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Aaron J Deutsch
    • , Buhm Han
    • , Xinli Hu
    • , Yukinori Okada
    •  & Soumya Raychaudhuri
  6. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Aaron J Deutsch
    • , Buhm Han
    • , Xinli Hu
    • , Yukinori Okada
    • , Shamil R Sunyaev
    •  & Soumya Raychaudhuri
  7. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.

    • Aaron J Deutsch
    •  & Xinli Hu
  8. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

    • Buhm Han
  9. Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

    • Yukinori Okada
  10. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Yukinori Okada
  11. Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

    • Stephen Eyre
    • , Jane Worthington
    •  & Soumya Raychaudhuri
  12. 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.

    • Stephen Eyre
    •  & Jane Worthington
  13. Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

    • Michael Knapp
  14. Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

    • Alexandra Zhernakova
    • , Javier Gutierrez-Achury
    •  & Cisca Wijmenga
  15. Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.

    • Tom W J Huizinga
  16. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo Abecasis
    •  & Lam C Tsoi
  17. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Gonçalo Abecasis
    •  & Lam C Tsoi
  18. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Jessica Becker
    • , Markus M Nöthen
    •  & Johannes Schumacher
  19. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Jessica Becker
    • , Markus M Nöthen
    •  & Johannes Schumacher
  20. Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.

    • Guy E Boeckxstaens
    •  & Mira M Wouters
  21. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Wei-Min Chen
    • , Suna Onengut-Gumuscu
    •  & Stephen S Rich
  22. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

    • Andre Franke
  23. Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Dafna D Gladman
  24. Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • Dafna D Gladman
  25. Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • Dafna D Gladman
  26. Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

    • Ines Gockel
  27. Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.

    • Javier Martin
  28. Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Rajan P Nair
    • , Philip E Stuart
    •  & James T Elder
  29. Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.

    • Proton Rahman
  30. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

    • Solbritt Rantapää-Dahlqvist
  31. Department of Rheumatology, Umeå University, Umeå, Sweden.

    • Solbritt Rantapää-Dahlqvist
  32. Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • David A van Heel
  33. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.

    • Lars Klareskog
    •  & Soumya Raychaudhuri
  34. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.

    • James T Elder
  35. Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA.

    • Peter K Gregersen
  36. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  37. Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker

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Contributions

T.L.L., A.J.D., S.R., P.I.W.d.B. and S.R.S. conceived the study, coordinated the study and wrote the initial version of the manuscript. T.L.L., A.J.D., S.R., B.H., X.H., Y.O., P.I.W.d.B. and S.R.S. contributed to the study design and analysis strategy. T.L.L., A.J.D. and S.R. conducted all analyses. The following authors organized and contributed subject samples and provided SNP genotype data: S.E., T.W.J.H., L.K., J.M., S.R.-D., J.W. and P.K.G. (rheumatoid arthritis); W.-M.C., S.O.-G. and S.S.R. (T1D); G.A., A.F., D.D.G., R.P.N., P.R., P.E.S., L.C.T. and J.T.E. (psoriasis); J.G.-A., D.A.v.H., A.Z. and C.W. (celiac disease); and J.B., G.E.B., I.G., M.K., M.M.N., M.M.W. and J.S. (achalasia). The following authors contributed to critical writing and review of the manuscript: X.H., D.A.v.H., M.K., S.E., S.S.R., L.K., A.Z., C.W., Y.O. and T.W.J.H. All authors contributed to the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Paul I W de Bakker or Soumya Raychaudhuri.

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DOI

https://doi.org/10.1038/ng.3379

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