Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases (original) (raw)

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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

1. Tobias L Lenz and Aaron J Deutsch: These authors contributed equally to this work.

Authors and 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. Department of Evolutionary Ecology, Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Ploen, Germany
   Tobias L Lenz
4. Division of Rheumatology, Department of Medicine, Immunology and Allergy, 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. Department of Medicine, Rheumatology Unit, 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

Authors

1. Tobias L Lenz
2. Aaron J Deutsch
3. Buhm Han
4. Xinli Hu
5. Yukinori Okada
6. Stephen Eyre
7. Michael Knapp
8. Alexandra Zhernakova
9. Tom W J Huizinga
10. Gonçalo Abecasis
11. Jessica Becker
12. Guy E Boeckxstaens
13. Wei-Min Chen
14. Andre Franke
15. Dafna D Gladman
16. Ines Gockel
17. Javier Gutierrez-Achury
18. Javier Martin
19. Rajan P Nair
20. Markus M Nöthen
21. Suna Onengut-Gumuscu
22. Proton Rahman
23. Solbritt Rantapää-Dahlqvist
24. Philip E Stuart
25. Lam C Tsoi
26. David A van Heel
27. Jane Worthington
28. Mira M Wouters
29. Lars Klareskog
30. James T Elder
31. Peter K Gregersen
32. Johannes Schumacher
33. Stephen S Rich
34. Cisca Wijmenga
35. Shamil R Sunyaev
36. Paul I W de Bakker
37. Soumya Raychaudhuri

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.

Corresponding authors

Correspondence toPaul I W de Bakker or Soumya Raychaudhuri.

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Competing interests

The authors declare no competing financial interests.

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Lenz, T., Deutsch, A., Han, B. et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.Nat Genet 47, 1085–1090 (2015). https://doi.org/10.1038/ng.3379

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• Received: 12 February 2015
• Accepted: 16 July 2015
• Published: 10 August 2015
• Issue date: September 2015
• DOI: https://doi.org/10.1038/ng.3379