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Class II HLA interactions modulate genetic risk for multiple sclerosis

Nature Genetics volume 47, pages 11071113 (2015) | Download Citation


Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

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We thank the individuals, nurses and referring physicians who participated in this study. This project was supported by the US National Institutes of Health (NS049477, NS26799, R01NS032830, RC2NS070340, R01NS067305 and RC2GM093080), the Wellcome Trust (085475/B/08/Z, 085475/Z/08/Z, 084702/Z/08/Z and 098051), the UK MS Society (857/07, 861/07, 862/07, 894/08, 898/08 and 955/11), the UK Medical Research Council (G0700061), Naomi Branson, the Sainsbury Foundation, NMSS (RG 4198-A-1 and 4680-A-1, FG 1938-A-1, JF2138A1, JF-2137A4 and South Florida chapter), the Cambridge National Institute for Health Research (NIHR) British Research Council (BRC), DeNDRon, the Bibbi and Niels Jensens Foundation, the Swedish Brain Foundation, the Swedish Research and County Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the AFA Foundation, the Foundation for Strategic Research, the Stockholm County Council (592229), the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet, the Swedish Council for Working Life and Social Research, INSERM, ARSEP, AFM, GIS-IBISA, BMBF, KKNMS (01GI0917), Deutsche Forschungsgemeinschaft (530/1-1), Munich Biotec Cluster M4, the Fidelity Biosciences Research Initiative, FWO-Vlaanderen, Research Fund KU Leuven (OT/11/087), the Belgian Neurological Society, the Belgian Charcot Foundation, Gemeinnützige Hertie Stiftung, CRPPMS University Zurich, the Danish MS Society, the Danish Council for Strategic Research, the Center of Excellence for Disease Genetics of the Academy of Finland, the Sigrid Juselius Foundation, the Helsinki University Central Hospital Research Foundation, FISM (2011/R/14), Fondazione Cariplo (2010-0728), MIUR (PRIN08), CRT Foundation Turin, the Italian Ministry of Health (502/92), the Italian Foundation for Multiple Sclerosis, INSPE, the Multiple Sclerosis Association of Oslo, the Norwegian Research Council (143153 and 143410), the South-Eastern Norwegian Health Authorities (51852/ILM) and the Australian National Health and Medical Research Council (633275 and 1053756).

We acknowledge the use of samples from the British 1958 Birth Cohort DNA collection (UK Medical Research Council, G0000934 and Wellcome Trust, 068545/Z/02), the UK National Blood Service controls, the Vanderbilt University Medical Center's BioVU DNA Resources Core (US National Institutes of Health, 1UL1RR024975-01), CRB-REFGENSEP, Norwegian Bone Marrow Registry controls, the Norwegian Multiple Sclerosis Registry and Biobank, NARCOMS Registry (CMSC), the Brigham and Women's Hospital PhenoGenetic Project and Academy of Finland DILGOM (136895, 263836 and 118065).

The GWAS made use of external control data from the popgen biobank, Swedish Breast Cancer study, HYPERGENES, CHOP, the Swedish CAD study, BRC-REFGENSEP, Pitié-Salpêtrière CIC, Généthon, the Wellcome Trust Sanger Institute, the University of Miami John P. Hussman Institute, ICM, the Norwegian Multiple Sclerosis Registry and Biobank, the SNP Technology Platform in Uppsala, Sweden, and the University of California, San Francisco. Full acknowledgments are included in the Supplementary Note.

Author information

Author notes

    • Loukas Moutsianas
    • , Luke Jostins
    •  & Ashley H Beecham

    These authors contributed equally to this work.

    • Stephen Sawcer
    •  & Gil McVean

    These authors jointly supervised this work.


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

    • Loukas Moutsianas
    • , Luke Jostins
    • , Alexander T Dilthey
    • , Dionysia K Xifara
    • , Peter Donnelly
    • , Chris C A Spencer
    •  & Gil McVean
  2. John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.

    • Ashley H Beecham
    • , Margaret A Pericak-Vance
    •  & Jacob L McCauley
  3. Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

    • Maria Ban
    • , Alastair Compston
    •  & Stephen Sawcer
  4. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Tejas S Shah
    • , Carl A Anderson
    •  & Jeffrey Barrett
  5. Program in Translational NeuroPsychiatric Genomics, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Nikolaos A Patsopoulos
    •  & Philip L De Jager
  6. Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Nikolaos A Patsopoulos
    •  & Philip L De Jager
  7. Harvard Medical School, Boston, Massachusetts, USA.

    • Nikolaos A Patsopoulos
    •  & Philip L De Jager
  8. Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.

    • Nikolaos A Patsopoulos
    • , Chris Cotsapas
    • , David A Hafler
    •  & Philip L De Jager
  9. Institute of Environmental Medicine (IMM), Karolinska Institutet, Stockholm, Sweden.

    • Lars Alfredsson
  10. Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.

    • Katherine E Attfield
    •  & Lars Fugger
  11. Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, San Francisco, California, USA.

    • Sergio E Baranzini
    • , Pierre-Antoine Gourraud
    • , Jorge R Oksenberg
    •  & Stephen L Hauser
  12. HLA Laboratory, Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Thomas M C Binder
  13. Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.

    • David Booth
    •  & Graeme Stewart
  14. Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

    • Dorothea Buck
    • , Bernhard Hemmer
    •  & Juliane Winkelmann
  15. Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway.

    • Elisabeth G Celius
    •  & Hanne F Harbo
  16. Department of Neurology and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Chris Cotsapas
    •  & David A Hafler
  17. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Chris Cotsapas
  18. Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

    • Sandra D'Alfonso
  19. Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.

    • Calliope A Dendrou
    •  & Lars Fugger
  20. Department of Neurosciences, Laboratory for Neuroimmunology, KU Leuven, Leuven, Belgium.

    • Bénédicte Dubois
    •  & An Goris
  21. INSERM, Université Pierre et Marie Curie, CNRS, Assistance Publique–Hôpitaux de Paris (AP-HP), Département des Maladies du Système Nerveux and UMRS 1127-7225, Institut Cerveau Moelle Spinal Cord and Brain Institute, Pitié-Salpêtrière, Paris, France.

    • Bertrand Fontaine
  22. Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University–Medical Center, Mainz, Germany.

    • Christiane Graetz
    • , Christina M Lill
    •  & Frauke Zipp
  23. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Bernhard Hemmer
    •  & Juliane Winkelmann
  24. German Competence Network Multiple Sclerosis (KKNMS), Munich, Germany.

    • Bernhard Hemmer
  25. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

    • Jan Hillert
    • , Ingrid Kockum
    •  & Tomas Olsson
  26. Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.

    • Stephen Leslie
  27. Department of Mathematics and Statistics, University of Melbourne, Parkville, Melbourne, Victoria, Australia.

    • Stephen Leslie
  28. Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.

    • Christina M Lill
  29. Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

    • Filippo Martinelli-Boneschi
  30. Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

    • Filippo Martinelli-Boneschi
  31. Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark.

    • Annette Oturai
    •  & Helle Bach Søndergaard
  32. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

    • Janna Saarela
  33. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

    • Anne Spurkland
  34. Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.

    • Bruce Taylor
  35. Institut für Humangenetik, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
  36. Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.

    • Juliane Winkelmann
  37. Department of Neurology and Neurological Sciences, Center for Sleep Sciences and Medicine, Stanford University, Stanford, California, USA.

    • Juliane Winkelmann
  38. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Jonathan L Haines
  39. Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.

    • David A Hafler
  40. Harvard NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Adrian J Ivinson
  41. University of Oslo, Oslo, Norway.

    • Hanne F Harbo


  1. the International Multiple Sclerosis Genetics Consortium



    A.C., A.O., A.S., B.D., B.F., B.H., B.T., C.G., C.M.L., D.A.H., D. Booth, D. Buck, E.G.C., F.M.-B., F.Z., G.S., H.F.H., I.K., IIBDGC, J.H., J.L.H., J.L.M., J.R.O., J.S., L.A., P.L.D.J., S.D'A., S.L.H., S.S., T.M.C.B. and T.O. were involved with case ascertainment and phenotyping. A.G., A.O., B.F., D. Booth, D. Buck, F.M.-B., H.B.S., H.F.H., I.K., J.L.M., J.R.O., M.B., P.L.D.J., S.D'A. and S.S. processed the DNA. A.O., B.F., D.A.H., H.B.S., IIBDGC, J.L.M., M.B., P.L.D.J. and S.S. conducted and supervised the genotyping of samples. A.H.B., A.T.D., C.A.A., C.C.A.S., C.C., D.K.X., G.M., J.L.H., J.L.M., L.F., L.J., L.M., M.B., N.A.P., P.D., P.L.D.J., P.-A.G., S.E.B., S.L., S.S. and T.S.S. performed the analysis. A.G., A.H.B., A.J.I., A.O., A.T.D., B.D., B.F., B.H., C.A.A., C.C.A.S., C.C., C.G., C.M.L., D. Booth, D. Buck, D.K.X., E.G.C., F.M.-B., F.Z., G.M., H.B.S., H.F.H., I.K., J.B., J.L.H., J.L.M., J.S., J.W., L.J., L.M., M.B., N.A.P., P.D., P.L.D.J., S.D'A., S.L., S.S., T.M.C.B. and T.S.S. collected and managed the project data. A.C., A.H.B., A.J.I., A.S., B.H., C.A.A., C.A.D., C.C.A.S., C.C., C.G., C.M.L., D.A.H., E.G.C., F.M.-B., F.Z., G.M., G.S., H.F.H., J.B., J.H., J.L.H., J.L.M., J.R.O., J.S., J.W., K.E.A., L.A., L.J., M.A.P.-V., M.B., N.A.P., P.D., P.L.D.J., S.D'A., S.L., S.L.H., S.S., T.M.C.B., T.O. and T.S.S. contributed to the study concept and design. All authors reviewed and approved the final manuscript.

    Competing interests

    A.T.D., P.D., S.L. and G.M. are partners in Peptide Groove, LLP, which commercializes HLA*IMP.

    Corresponding author

    Correspondence to Gil McVean.

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