Letter | Published:

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Nature volume 476, pages 214219 (11 August 2011) | Download Citation


Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2,3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5,6,7,8,9,10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

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The principal funding for this study was provided by the Wellcome Trust (085475/B/08/Z, 085475/Z/08/Z, 075491/Z/04/Z and 068545/Z/02). The work was also supported by National Institutes of Health (AI076544, NS032830, NS049477, NS19142, NS049510, NS26799, NS43559, NS067305, CA104021, RR020092, RR024992 and K23N/S048869), US National Multiple Sclerosis Society (RG 4201-A-1), Nancy Davis Foundation, Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G0700061, G0000934), Multiple Sclerosis Society of Great Britain and Northern Ireland (898/08), Wolfson Royal Society Merit Award, Peter Doherty fellowship, Lagrange Fellowship, Harry Weaver Neuroscience Scholarships, Australian National Health and Medical Research Council (NHMRC), Australian Research Council Linkage Program Grant, JHH Charitable Trust Fund, Multiple Sclerosis Research Australia, Health Research Council New Zealand, National MS Society of New Zealand, Wetenschappelijk Onderzoek Multiple Sclerose, Bayer Chair on Fundamental Genetic Research regarding the Neuroimmunological Aspects of Multiple Sclerosis, Biogen Idec Chair Translational Research in Multiple Sclerosis, FWO-Vlaanderen, Belgian Neurological Society, Danish Multiple Sclerosis Society, Neuropromise EU grant (LSHM-CT-2005-018637), Center of Excellence for Disease Genetics of the Academy of Finland, Sigrid Juselius Foundation, Helsinki University Central Hospital Research Foundation, Bundesministerium für Bildung und Technologie (KKNMS consortium Control MS), Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche sur la Sclérose En Plaques (ARSEP), Association Française contre les Myopathies (AFM), Italian Foundation for Multiple Sclerosis (FISM grants 2002/R/40, 2005/R/10, 2008/R/11 and 2008/R/15), Italian Ministry of Health (grant Giovani Ricercatori 2007 - D.lgs 502/92), Regione Piemonte (grants 2003, 2004, 2008, 2009), CRT Foundation, Turin, Moorfields/UCL Institute of Ophthalmology NIHR Biomedical Research Centre, Norwegian MS Register and Biobank, Research Council of Norway, South-Eastern and Western Norway regional Health Authories, Ullevål University Hospital Scientific Advisory Council, Haukeland University Hospital, Amici Centro Sclerosi Multipla del San Raffaele (ACESM), Association of British Neurologists, Spanish Ministry of Health (FISPI060117), Bibbi and Niels Jensens Foundation, Montel Williams foundation, Hjärnfonden and Swedish medical research council (8691), Stockholm County Council (562183), Swedish Council for Working life and Social Research, Gemeinnützige Hertie Stiftung, Northern California Kaiser Permanente members and Polpharma Foundation, and Washington University Institute of Clinical and Translational Sciences—Brain, Behavioral and Performance Unit. We acknowledge use of data from the British 1958 Birth Cohort, the UK National Blood Service, the popgen biobank, the KORA and MONICA Augsburg studies, the Accelerated Cure Project, the Brigham & Women’s Hospital PhenoGenetic Project, the Swedish CAD project, the Norwegian Bone Marrow Donor Registry, the Children’s Hospital of Philadelphia (CHOP), the Swedish Breast Cancer study, BRC-REFGENSEP (Pitié-Salpêtrière Centre d’Investigation Clinique (CIC) and Généthon) and HYPERGENES (HEALTH-F4-2007-201550). Projects received support from the German Ministry of Education and Research, the Helmholtz Zentrum München—National Research Center, the German National Genome Research Network (NGFN), the LMUinnovativ, the Knut and Alice Wallenberg Foundation, the Center for Applied Genomics from the Children’s Hospital of Philadelphia Development Award, the Agency for Science & Technology and Research of Singapore, and the Susan G. Komen Breast Cancer Foundation. We thank S. Bertrand, J. Bryant, S. L. Clark, L. Collimedaglia, G. Coniglio, J. S. Conquer, B. Colombo, T. Dibling, G. Eckstein, J. C. Eldred, G. Fischer, S. Gamble, P. Gregersen, R. Guerrero, C. Hind, P. Lichtner, L. Moiola, H. Mousavi, R. Naismith, R. J. Parks, R. Pearson, V. Pilato, M. Radaelli, E. Scarpini, C. R. Stribling, T. Strom, S. Taylor, D. Vukcevic and A. Wilk for their help and support. Detailed acknowledgements are available in Supplementary Information. This manuscript is dedicated to the memory of L. Peltonen, a member of both the IMSGC and the WTCCC2, in recognition of her contributions to, and her leadership in, human genetics.

Author information

Author notes

    • Stephen Sawcer
    • , Garrett Hellenthal
    • , Matti Pirinen
    • , Chris C. A. Spencer
    • , Peter Donnelly
    •  & Alastair Compston

    These authors contributed equally to this work.

    • Leena Peltonen



  1. University of Cambridge, Department of Clinical Neurosciences, Addenbrooke’s Hospital, BOX 165, Hills Road, Cambridge CB2 0QQ, UK.

    • Stephen Sawcer
    • , Maria Ban
    • , Anu Kemppinen
    • , Amie Baker
    • , Sheila Skidmore
    •  & Alastair Compston
  2. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Garrett Hellenthal
    • , Matti Pirinen
    • , Chris C. A. Spencer
    • , Zhan Su
    • , Colin Freeman
    • , Gavin Band
    • , Amy Strange
    • , Céline Bellenguez
    • , Eleni Giannoulatou
    • , Anna Rautanen
    • , Gil McVean
    •  & Peter Donnelly
  3. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Nikolaos A. Patsopoulos
    •  & Paul I. W. de Bakker
  4. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, 02142 Massachusetts, USA.

    • Nikolaos A. Patsopoulos
    • , Kristin Ardlie
    • , Cristin Aubin
    • , Mark J. Daly
    • , Paul I. W. de Bakker
    • , Philip L. De Jager
    •  & David A. Hafler
  5. Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Nikolaos A. Patsopoulos
    • , Susan Pobywajlo
    •  & Philip L. De Jager
  6. Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.

    • Loukas Moutsianas
    • , Alexander Dilthey
    •  & Peter Donnelly
  7. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Sarah E. Hunt
    • , Sarah Edkins
    • , Emma Gray
    • , Simon C. Potter
    • , Matthew Gillman
    • , Rhian Gwilliam
    • , Alagurevathi Jayakumar
    • , Hannah Blackburn
    • , Jennifer Liddle
    • , Marc L. Perez
    • , Matthew J. Waller
    • , Michelle Ricketts
    • , Naomi Hammond
    • , Owen T. McCann
    • , Pamela Whittaker
    • , Paul Weston
    • , Sara Widaa
    • , Serge Dronov
    • , Suzannah J. Bumpstead
    • , Rathi Ravindrarajah
    • , Aarno Palotie
    • , Panos Deloukas
    •  & Cordelia Langford
  8. Westmead Millennium Institute, University of Sydney, New South Wales 2145, Australia.

    • David R. Booth
    • , Rob N. Heard
    •  & Graeme J. Stewart
  9. Laboratory for Neuroimmunology, Section of Experimental Neurology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.

    • An Goris
    • , Katleen Clysters
    • , Rita Dobosi
    •  & Bénédicte Dubois
  10. Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark.

    • Annette Bang Oturai
    • , Finn Sellebjerg
    • , Per Soelberg Sørensen
    •  & Helle Bach Søndergaard
  11. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.

    • Janna Saarela
    • , Virpi Leppä
    • , Aarno Palotie
    •  & Anna-Maija Sulonen
  12. INSERM UMR S 975 CRICM, UPMC, Département de neurologie Pitié-Salpêtrière, AP-HP, 75013 Paris, France.

    • Bertrand Fontaine
    • , Isabelle Cournu-Rebeix
    •  & Claire Fontenille
  13. Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

    • Bernhard Hemmer
    • , Achim Berthele
    • , Dorothea Buck
    • , Sabine Cepok
    • , Muna Hoshi
    •  & Juliane Winkelmann
  14. Department of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

    • Frauke Zipp
  15. Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.

    • Frauke Zipp
  16. Institute for Neuroimmunology and Clinical MS Research (inims), Centre for Molecular Neurobiology, Falkenried 94, D-20251 Hamburg, Germany.

    • Roland Martin
    •  & Sabine Roesner
  17. Department of Clinical Pharmacology, University of Oxford, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK.

    • Stephen Leslie
  18. Queen’s University Belfast, University Road, Belfast BT7 1NN, Northern Ireland, UK.

    • Stanley Hawkins
  19. Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, 28100 Novara, Italy.

    • Sandra D’alfonso
    •  & Laura Bergamaschi
  20. Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

    • Filippo Martinelli Boneschi
    • , Giancarlo Comi
    • , Federica Esposito
    • , Vittorio Martinelli
    •  & Mariaemma Rodegher
  21. Department of Neurology, Oslo University Hospital, N-0407 Oslo, Norway.

    • Hanne F. Harbo
    • , Elisabeth G. Celius
    • , Inger-Lise Mero
    •  & Cathrine Smestad
  22. Department of Neurology, University of Oslo, N-0318 Oslo, Norway.

    • Hanne F. Harbo
    •  & Åslaug R. Lorentzen
  23. Institute of Basal Medical Sciences, University of Oslo, N-0317 Oslo, Norway.

    • Anne Spurkland
  24. Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland.

    • Marcin P. Mycko
    • , Krzysztof W. Selmaj
    •  & Ewa Tronczynska
  25. Clinical Neuroinmunology Unit, Multiple Sclerosis Center of Catalonia (CEM-Cat), Vall d’Hebron University Hospital, Barcelona 08035, Spain.

    • Manuel Comabella
    •  & Xavier Montalban
  26. Department of Clinical Neurosciences, Centre for Molecular Medicine CMM, L8:04, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

    • Ingrid Kockum
    • , Maja Jagodic
    • , Izaura Lima Bomfim
    • , Jenny Link
    • , Fredrik Piehl
    • , Emilie Sundqvist
    • , Tomas Olsson
    •  & Jan Hillert
  27. Keele University Medical School, Stoke-on-Trent ST4 7NY, UK.

    • Clive Hawkins
    • , Roby Abraham
    • , Tania Mihalova
    •  & Richard C. Strange
  28. Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Clinical Neurology Research Group, Tamar Science Park, Plymouth PL6 8BX, UK.

    • John Zajicek
    • , Jeremy Hobart
    • , Wendy Ingram
    •  & Jane Vickery
  29. Department of Neurology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK.

    • Neil Robertson
    • , Katharine Baker
    • , Mark Cossburn
    • , Gillian Ingram
    •  & Trevor Pickersgill
  30. Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, California 94720-7356, USA.

    • Lisa F. Barcellos
    • , Hong L. Quach
    •  & Patricia P. Ramsay
  31. Kaiser Permanente Northern California Division of Research, 2000 Broadway, Oakland, California 94612, USA.

    • Lisa F. Barcellos
    • , Allan Bernstein
    • , Catherine A. Schaefer
    • , Ling Shen
    •  & Brigid Simms-Acuna
  32. Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden.

    • Lars Alfredsson
  33. Department of Neurology, University of California San Francisco, 505 Parnassus Avenue, S-256, San Francisco, California 94143-0435, USA.

    • Sergio E. Baranzini
    • , Bruce A. C. Cree
    • , Refujia Gomez
    • , Robin R. Lincoln
    • , Adam Santaniello
    • , Jorge R. Oksenberg
    •  & Stephen L. Hauser
  34. Neurological Institute C. Mondino, IRCCS, 27100 Pavia, Italy.

    • Roberto Bergamaschi
  35. The Walton Centre for Neurology and Neurosurgery, Liverpool L7 9LJ, UK.

    • Mike Boggild
  36. Center for Applied Genomics, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA.

    • Jonathan P. Bradfield
    • , Rosetta Chiavacci
    • , Joseph Glessner
    • , Struan F. A. Grant
    • , Hakon Hakonarson
    • , Cecilia Kim
    • , Frank Mentch
    • , Patrick M. A. Sleiman
    • , Kai Wang
    •  & Haitao Zhang
  37. INSERM U 1043 et Pôle Neurosciences, Hopital Purpan, 31059 Toulouse, France.

    • David Brassat
  38. School of Medicine, Griffith University, 4222, Australia.

    • Simon A. Broadley
  39. Florey Neuroscience Institutes, University of Melbourne, Victoria 3010, Australia.

    • Helmut Butzkueven
    • , Trevor J. Kilpatrick
    • , Mark Marriott
    •  & Justin P. Rubio
  40. Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

    • Helmut Butzkueven
    • , Trevor J. Kilpatrick
    • , Mark Marriott
    •  & Niall Tubridy
  41. Box Hill Hospital, Monash University, Box Hill 3128, Australia.

    • Helmut Butzkueven
  42. Department of Medicine, RMH Cluster, University of Melbourne, Victoria 3010, Australia.

    • Helmut Butzkueven
  43. Multiple Sclerosis Centre, Department of Neurology, Ospedali Civili di Brescia, 25018 Brescia, Italy.

    • Ruggero Capra
  44. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia 6009, Australia.

    • William M. Carroll
    •  & Allan G. Kermode
  45. Department of Neurosciences, University of Turin, A.O.U. San Giovanni Battista, 10126 Turin, Italy.

    • Paola Cavalla
  46. INSERM U669, Univ Paris-Sud, 94800 Villejuif, France.

    • Françoise Clerget-Darpoux
  47. University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia.

    • Mathew B. Cox
    • , Jeannette S. Lechner-Scott
    •  & Rodney J. Scott
  48. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 1441 Eastlake Ave. Room 4453, Los Angeles, California 90033, USA.

    • Wendy Cozen
    • , Talat Islam
    •  & Thomas Mack
  49. Department of Neurology, Washington University, St Louis, Missouri 63110, USA.

    • Anne H. Cross
    •  & Laura Piccio
  50. University of Milan, Department of Medicine, Surgery and Dentistry, AO San Paolo, University of Milan, c/o Filarete Foundation, Viale Ortles 22/4, 20139 Milano, Italy.

    • Daniele Cusi
    • , Sara Lupoli
    • , Fabio Macciardi
    •  & Erika Salvi
  51. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Mark J. Daly
    • , Adrian J. Ivinson
    •  & Philip L. De Jager
  52. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Mark J. Daly
  53. The UK DNA Banking Network, Centre for Integrated Genomic Medical Research, University of Manchester M13 9PT, UK.

    • Emma Davis
    • , Katherine Dixon
    •  & William Ollier
  54. Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands.

    • Paul I. W. de Bakker
  55. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands.

    • Paul I. W. de Bakker
  56. Service de Neurologie, Hôpital Central, 54035 Nancy, France.

    • Marc Debouverie
  57. National Multiple Sclerosis Center, 1820 Melsbroek, Belgium.

    • Marie Beatrice D’hooghe
  58. Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, D-24105, Germany.

    • David Ellinghaus
    • , Andre Franke
    • , Stefan Schreiber
    •  & Michael Wittig
  59. Department of Neurology, Tampere University Hospital, FIN-33014 Tampere, Finland.

    • Irina Elovaara
  60. University of Tampere, Medical School, Tampere 33014, Finland.

    • Irina Elovaara
  61. Menzies Research Institute Tasmania, University of Tasmania, Private Bag 23, Hobart, Tasmania 7000, Australia.

    • Simon Foote
    • , Jim Stankovich
    •  & Bruce Taylor
  62. Department of Neurological Sciences, Centro Dino Ferrari, University of Milan, Fondazione Cà Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.

    • Daniela Galimberti
  63. Centro Studi Sclerosi Multipla, Ospedale di Gallarate, 21013 Gallarate (VA), Italy.

    • Angelo Ghezzi
  64. Service de Neurologie, Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France.

    • Olivier Gout
  65. Belfast Health and Social Care Trust, City Hospital, Belfast BT9 7AB, Northern Ireland, UK.

    • Colin Graham
  66. Division of Genetics, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA.

    • Struan F. A. Grant
    • , Hakon Hakonarson
    • , Patrick M. A. Sleiman
    • , Kai Wang
    •  & Haitao Zhang
  67. Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 Civic Center Blvd., Philadelphia, Pennsylvania 19104, USA.

    • Struan F. A. Grant
    •  & Hakon Hakonarson
  68. Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, 20148 Milan, Italy.

    • Franca Rosa Guerini
  69. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden.

    • Per Hall
  70. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine, L8:03, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden.

    • Anders Hamsten
    •  & Malin Larsson
  71. Department of Neurology, Heinrich-Heine-University, D-40225, Düsseldorf, Germany.

    • Hans-Peter Hartung
  72. Commissariat à l’énergie atomique, Institut de Génomique, Centre National de Genotypage, 2 rue Gaston Cremieux, CP 5721, 91057 Evry Cedex, France.

    • Simon Heath
    •  & Mark Lathrop
  73. Experimental and Clinical Research Center, Charité, Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin 13125, Germany.

    • Carmen Infante-Duarte
  74. Department for Paediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Carl-Neuberg Strasse 1, D30625 Hannover, Germany.

    • Michael Kabesch
  75. Centre for Neuroscience, University of Melbourne, Victoria 3010, Australia.

    • Trevor J. Kilpatrick
  76. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Munich, Germany.

    • Norman Klopp
    • , Ina-Maria Rückert
    •  & H-Erich Wichmann
  77. Seinäjoki Central Hospital, Seinäjoki, 60220, Finland.

    • Keijo Koivisto
  78. Hunter Medical Research Institute, John Hunter Hospital, Lookout Road, New Lambton, New South Wales 2305, Australia.

    • Jeannette S. Lechner-Scott
  79. SCDU Neurology, Maggiore della Carità Hospital, 28100 Novara, Italy.

    • Maurizio A. Leone
    •  & Paola Naldi
  80. Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki 00290, Finland.

    • Virpi Leppä
    •  & Anna-Maija Sulonen
  81. Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Entrance 70, 3rd Floor, Res Dept 2, Univeristy Hospital, S-75185 Uppsala, Sweden.

    • Ulrika Liljedahl
    •  & Ann-Christine Syvänen
  82. Human Genetics and Cancer Biology, Genome Institute of Singapore, Singapore 138672.

    • Jianjun Liu
  83. Institute of Immunology, Oslo University Hospital, N-0027 Oslo, Norway.

    • Åslaug R. Lorentzen
    •  & Inger-Lise Mero
  84. Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

    • Sara Lupoli
  85. Department of Psychiatry and Human Behavior, University of California, Irvine (UCI), 5251 California Av, S.te 240, Irvine, California 92617, USA.

    • Fabio Macciardi
  86. Christchurch School of Medicine, University of Otago, Christchurch 8041, New Zealand.

    • Deborah Mason
  87. John P. Hussman Institute for Human Genomics and The Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, 1501 NW 10th Avenue, Miami, Florida 33136, USA.

    • Jacob L. McCauley
    •  & Margaret A. Pericak-Vance
  88. Greater Manchester Centre for Clinical Neurosciences, Hope Hospital, Salford M6 8HD, UK.

    • John Mottershead
  89. The Department of Neurology, Dunedin Public Hospital, Otago 9016, New Zealand.

    • John Mottershead
  90. The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway.

    • Kjell-Morten Myhr
  91. Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway.

    • Kjell-Morten Myhr
  92. Plymouth Hospitals NHS Trust, Department of Neurology, Derriford Hospital, Plymouth PL6 8DH, UK.

    • Alison Page
  93. Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki 00014, Finland.

    • Aarno Palotie
  94. Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Aarno Palotie
  95. Pôle Neurosciences Cliniques,Service de Neurologie, Hôpital de la Timone, 13005 Marseille, France.

    • Jean Pelletier
  96. Department Neurology, Oulu University Hospital, Oulu 90029, Finland.

    • Mauri Reunanen
  97. UK MS Tissue Bank, Wolfson Neuroscience Laboratories, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.

    • Richard Reynolds
  98. Université de Montréal & Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.

    • John D. Rioux
  99. Neurology and Center for Experimental Neurological Therapy (CENTERS), Sapienza University of Rome, 00189-Rome, Italy.

    • Marco Salvetti
  100. KOS Genetic Srl, Via Podgora, 7, 20123 Milan, Italy.

    • Erika Salvi
    •  & Francesca Taddeo
  101. Department of General Internal Medicine, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, Kiel 24105, Germany.

    • Stefan Schreiber
  102. Systems Biology and Protein-Protein Interaction, Center for Molecular Neurobiology, Falkenried 94, D-20251 Hamburg, Germany.

    • Christian Schulze
  103. Center for Human Genetics Research, Vanderbilt University Medical Center, 519 Light Hall, Nashville, Tennessee 37232, USA.

    • David Sexton
    • , Rebecca Zuvich
    •  & Jonathan L. Haines
  104. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, Western Australia 6008, Australia.

    • Jenefer M. Blackwell
  105. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK.

    • Jenefer M. Blackwell
  106. Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, FIN-00290 Helsinki, Finland.

    • Pentti Tienari
  107. Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AF, UK.

    • Elvira Bramon
  108. Service de Neurologie et Faculté de Médecine de Reims, Université de Reims Champagne-Ardenne, 51100 Reims, France.

    • Ayman Tourbah
  109. University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.

    • Matthew A. Brown
  110. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

    • Juan P. Casas
  111. St. Vincent’s University Hospital, Dublin 4, Ireland.

    • Niall Tubridy
  112. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Eire.

    • Aiden Corvin
  113. Centre for Gastroenterology, Bart’s and the London School of Medicine and Dentistry, London E1 2AT, UK.

    • Janusz Jankowski
  114. Department of Neurosciences, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, 08036, Spain.

    • Pablo Villoslada
  115. Clinical Neurosciences, St George’s University of London, London SW17 0RE, UK.

    • Hugh S. Markus
  116. Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK.

    • Christopher G. Mathew
    •  & Richard C. Trembath
  117. Medical Research Council Biostatistics Unit, Robinson Way, Cambridge CB2 0SR, UK.

    • James Wason
  118. Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

    • Colin N. A. Palmer
  119. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.

    • H-Erich Wichmann
  120. Klinikum Grosshadern, Munich 81377, Germany.

    • H-Erich Wichmann
  121. King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK.

    • Robert Plomin
  122. Department of Neurology, Auckland City Hospital, Grafton Road, Auckland 1010, New Zealand.

    • Ernest Willoughby
  123. Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.

    • Juliane Winkelmann
  124. Institut für Humangenetik, Helmholtz Zentrum München, 85764 Neuherberg, Munich, Germany.

    • Juliane Winkelmann
  125. Popgen Biobank, Christian-Albrechts University Kiel, Kiel 24105, Germany.

    • Michael Wittig
  126. Pôle Recherche et Santé Publique, CHU Pontchaillou, 35033 Rennes, France.

    • Jacqueline Yaouanq
  127. NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.

    • Ananth C. Viswanathan
  128. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

    • Nicholas W. Wood
  129. Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE, UK.

    • Audrey Duncanson
  130. Harvard NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Adrian J. Ivinson
  131. Department of Neurology & Immunology, Yale University Medical School, New Haven, 06520 Connecticut, USA.

    • David A. Hafler


  1. The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2

    A list of authors and their affiliations appears at the end of the paper; membership of both consortia is listed in Supplementary Information.



    Details of individual contributions are listed in Supplementary Information.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Peter Donnelly or Alastair Compston.

    Supplementary information

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      Supplementary Information

      The file contains Supplementary Text, Supplementary Tables 1-39, Supplementary Figures 1-35 with legends and additional references (see table of contents).

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      Supplementary Data

      The file contains Supplementary Data, comprising of Supplementary Tables A-C.

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