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

Nature volume 476, pages 214–219 (2011)Cite this article

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Abstract

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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Figure 1: Distribution of cases and controls.
Figure 2: Regions of the genome showing association to multiple sclerosis.
Figure 3: Graphic representation of the T-helper-cell differentiation pathway.
Figure 4: Results for the main MHC alleles.

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Acknowledgements

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

  1. Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C. A. Spencer, Peter Donnelly and Alastair Compston: These authors contributed equally to this work.

  2. Leena Peltonen: Deceased.

Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Cambridge, 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, 02115, Massachusetts, 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. Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, 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. Department of Neurology, Danish Multiple Sclerosis Center, 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. Département de neurologie Pitié-Salpêtrière, INSERM UMR S 975 CRICM, UPMC, 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, Division of Neuroscience, Institute of Experimental Neurology (INSPE), 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. Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, 94720-7356, California, USA

    Lisa F. Barcellos, Hong L. Quach & Patricia P. Ramsay

  31. Kaiser Permanente Northern California Division of Research, 2000 Broadway, Oakland, 94612, California, 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, 94143-0435, California, 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, 19104, Pennsylvania, 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. Department of Neurology, Multiple Sclerosis Centre, 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, 90033, California, USA

    Wendy Cozen, Talat Islam & Thomas Mack

  49. Department of Neurology, Washington University, St Louis, 63110, Missouri, USA

    Anne H. Cross & Laura Piccio

  50. Department of Medicine, University of Milan, 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, 02115, Massachusetts, USA

    Mark J. Daly, Adrian J. Ivinson & Philip L. De Jager

  52. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, 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, 19104, Pennsylvania, 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, 19104, Pennsylvania, 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. Department of Medicine Solna, Atherosclerosis Research Unit, 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. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, 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, 92617, California, 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, 33136, Florida, 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. Department of Neurology, The Norwegian Multiple Sclerosis Competence Centre, 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. Department of Neurology, Plymouth Hospitals NHS Trust, 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, 02142, Massachusetts, 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, 02115, Massachusetts, USA

    Adrian J. Ivinson

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

    David A. Hafler

Consortia

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

  • Stephen Sawcer
  • , Garrett Hellenthal
  • , Matti Pirinen
  • , Chris C. A. Spencer
  • , Nikolaos A. Patsopoulos
  • , Loukas Moutsianas
  • , Alexander Dilthey
  • , Zhan Su
  • , Colin Freeman
  • , Sarah E. Hunt
  • , Sarah Edkins
  • , Emma Gray
  • , David R. Booth
  • , Simon C. Potter
  • , An Goris
  • , Gavin Band
  • , Annette Bang Oturai
  • , Amy Strange
  • , Janna Saarela
  • , Céline Bellenguez
  • , Bertrand Fontaine
  • , Matthew Gillman
  • , Bernhard Hemmer
  • , Rhian Gwilliam
  • , Frauke Zipp
  • , Alagurevathi Jayakumar
  • , Roland Martin
  • , Stephen Leslie
  • , Stanley Hawkins
  • , Eleni Giannoulatou
  • , Sandra D’alfonso
  • , Hannah Blackburn
  • , Filippo Martinelli Boneschi
  • , Jennifer Liddle
  • , Hanne F. Harbo
  • , Marc L. Perez
  • , Anne Spurkland
  • , Matthew J. Waller
  • , Marcin P. Mycko
  • , Michelle Ricketts
  • , Manuel Comabella
  • , Naomi Hammond
  • , Ingrid Kockum
  • , Owen T. McCann
  • , Maria Ban
  • , Pamela Whittaker
  • , Anu Kemppinen
  • , Paul Weston
  • , Clive Hawkins
  • , Sara Widaa
  • , John Zajicek
  • , Serge Dronov
  • , Neil Robertson
  • , Suzannah J. Bumpstead
  • , Lisa F. Barcellos
  • , Rathi Ravindrarajah
  • , Roby Abraham
  • , Lars Alfredsson
  • , Kristin Ardlie
  • , Cristin Aubin
  • , Amie Baker
  • , Katharine Baker
  • , Sergio E. Baranzini
  • , Laura Bergamaschi
  • , Roberto Bergamaschi
  • , Allan Bernstein
  • , Achim Berthele
  • , Mike Boggild
  • , Jonathan P. Bradfield
  • , David Brassat
  • , Simon A. Broadley
  • , Dorothea Buck
  • , Helmut Butzkueven
  • , Ruggero Capra
  • , William M. Carroll
  • , Paola Cavalla
  • , Elisabeth G. Celius
  • , Sabine Cepok
  • , Rosetta Chiavacci
  • , Françoise Clerget-Darpoux
  • , Katleen Clysters
  • , Giancarlo Comi
  • , Mark Cossburn
  • , Isabelle Cournu-Rebeix
  • , Mathew B. Cox
  • , Wendy Cozen
  • , Bruce A. C. Cree
  • , Anne H. Cross
  • , Daniele Cusi
  • , Mark J. Daly
  • , Emma Davis
  • , Paul I. W. de Bakker
  • , Marc Debouverie
  • , Marie Beatrice D’hooghe
  • , Katherine Dixon
  • , Rita Dobosi
  • , Bénédicte Dubois
  • , David Ellinghaus
  • , Irina Elovaara
  • , Federica Esposito
  • , Claire Fontenille
  • , Simon Foote
  • , Andre Franke
  • , Daniela Galimberti
  • , Angelo Ghezzi
  • , Joseph Glessner
  • , Refujia Gomez
  • , Olivier Gout
  • , Colin Graham
  • , Struan F. A. Grant
  • , Franca Rosa Guerini
  • , Hakon Hakonarson
  • , Per Hall
  • , Anders Hamsten
  • , Hans-Peter Hartung
  • , Rob N. Heard
  • , Simon Heath
  • , Jeremy Hobart
  • , Muna Hoshi
  • , Carmen Infante-Duarte
  • , Gillian Ingram
  • , Wendy Ingram
  • , Talat Islam
  • , Maja Jagodic
  • , Michael Kabesch
  • , Allan G. Kermode
  • , Trevor J. Kilpatrick
  • , Cecilia Kim
  • , Norman Klopp
  • , Keijo Koivisto
  • , Malin Larsson
  • , Mark Lathrop
  • , Jeannette S. Lechner-Scott
  • , Maurizio A. Leone
  • , Virpi Leppä
  • , Ulrika Liljedahl
  • , Izaura Lima Bomfim
  • , Robin R. Lincoln
  • , Jenny Link
  • , Jianjun Liu
  • , Åslaug R. Lorentzen
  • , Sara Lupoli
  • , Fabio Macciardi
  • , Thomas Mack
  • , Mark Marriott
  • , Vittorio Martinelli
  • , Deborah Mason
  • , Jacob L. McCauley
  • , Frank Mentch
  • , Inger-Lise Mero
  • , Tania Mihalova
  • , Xavier Montalban
  • , John Mottershead
  • , Kjell-Morten Myhr
  • , Paola Naldi
  • , William Ollier
  • , Alison Page
  • , Aarno Palotie
  • , Jean Pelletier
  • , Laura Piccio
  • , Trevor Pickersgill
  • , Fredrik Piehl
  • , Susan Pobywajlo
  • , Hong L. Quach
  • , Patricia P. Ramsay
  • , Mauri Reunanen
  • , Richard Reynolds
  • , John D. Rioux
  • , Mariaemma Rodegher
  • , Sabine Roesner
  • , Justin P. Rubio
  • , Ina-Maria Rückert
  • , Marco Salvetti
  • , Erika Salvi
  • , Adam Santaniello
  • , Catherine A. Schaefer
  • , Stefan Schreiber
  • , Christian Schulze
  • , Rodney J. Scott
  • , Finn Sellebjerg
  • , Krzysztof W. Selmaj
  • , David Sexton
  • , Ling Shen
  • , Brigid Simms-Acuna
  • , Sheila Skidmore
  • , Patrick M. A. Sleiman
  • , Cathrine Smestad
  • , Per Soelberg Sørensen
  • , Helle Bach Søndergaard
  • , Jim Stankovich
  • , Richard C. Strange
  • , Anna-Maija Sulonen
  • , Emilie Sundqvist
  • , Ann-Christine Syvänen
  • , Francesca Taddeo
  • , Bruce Taylor
  • , Jenefer M. Blackwell
  • , Pentti Tienari
  • , Elvira Bramon
  • , Ayman Tourbah
  • , Matthew A. Brown
  • , Ewa Tronczynska
  • , Juan P. Casas
  • , Niall Tubridy
  • , Aiden Corvin
  • , Jane Vickery
  • , Janusz Jankowski
  • , Pablo Villoslada
  • , Hugh S. Markus
  • , Kai Wang
  • , Christopher G. Mathew
  • , James Wason
  • , Colin N. A. Palmer
  • , H-Erich Wichmann
  • , Robert Plomin
  • , Ernest Willoughby
  • , Anna Rautanen
  • , Juliane Winkelmann
  • , Michael Wittig
  • , Richard C. Trembath
  • , Jacqueline Yaouanq
  • , Ananth C. Viswanathan
  • , Haitao Zhang
  • , Nicholas W. Wood
  • , Rebecca Zuvich
  • , Panos Deloukas
  • , Cordelia Langford
  • , Audrey Duncanson
  • , Jorge R. Oksenberg
  • , Margaret A. Pericak-Vance
  • , Jonathan L. Haines
  • , Tomas Olsson
  • , Jan Hillert
  • , Adrian J. Ivinson
  • , Philip L. De Jager
  • , Leena Peltonen
  • , Graeme J. Stewart
  • , David A. Hafler
  • , Stephen L. Hauser
  • , Gil McVean
  • , Peter Donnelly
  •  & Alastair Compston

Contributions

Details of individual contributions are listed in Supplementary Information.

Corresponding authors

Correspondence to Peter Donnelly or Alastair Compston.

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Competing interests

The author declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary Information

The file contains Supplementary Text, Supplementary Tables 1-39, Supplementary Figures 1-35 with legends and additional references (see table of contents). (PDF 3691 kb)

Supplementary Data

The file contains Supplementary Data, comprising of Supplementary Tables A-C. (XLS 183 kb)

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The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). https://doi.org/10.1038/nature10251

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