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

      research-article
      The International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), 1 , 2 , 2 , 2 , 3 , 5 , 6 , 6 , 2 , 2 , 7 , 7 , 7 , 8 , 7 , 9 , 2 , 10 , 2 , 11 , 2 , 12 , 7 , 13 , 7 , 14 , 15 , 7 , 16 , 17 , 18 , 2 , 19 , 7 , 20 , 7 , 21 , 22 , 7 , 23 , 7 , 24 , 7 , 25 , 7 , 26 , 7 , 1 , 7 , 1 , 7 , 27 , 7 , 28 , 7 , 29 , 7 , 30 , 31 , 7 , 27 , 32 , 4 , 4 , 1 , 29 , 33 , 19 , 34 , 31 , 13 , 35 , 36 , 37 , 38 , 13 , 39 , 42 , 43 , 44 , 45 , 21 , 13 , 36 , 46 , 9 , 20 , 29 , 12 , 47 , 48 , 33 , 49 , 50 , 4 , 51 , 52 , 53 , 3 , 4 , 54 , 55 , 56 , 57 , 53 , 9 , 9 , 58 , 59 , 60 , 20 , 12 , 61 , 58 , 62 , 63 , 36 , 33 , 64 , 65 , 36 , 66 , 67 , 68 , 36 , 66 , 67 , 69 , 70 , 71 , 8 , 72 , 28 , 13 , 73 , 29 , 28 , 48 , 26 , 74 , 44 , 39 , 40 , 75 , 36 , 76 , 77 , 70 , 72 , 47 , 78 , 79 , 11 , 80 , 81 , 26 , 33 , 26 , 82 , 22 , 83 , 50 , 84 , 50 , 85 , 48 , 39 , 40 , 20 , 86 , 87 , 36 , 21 , 83 , 27 , 25 , 88 , 89 , 90 , 91 , 79 , 53 , 92 , 7 , 11 , 93 , 94 , 95 , 49 , 29 , 26 , 5 , 30 , 30 , 96 , 97 , 98 , 20 , 16 , 39 , 76 , 99 , 50 , 100 , 33 , 31 , 58 , 101 , 102 , 47 , 10 , 24 , 103 , 31 , 31 , 1 , 36 , 66 , 21 , 10 , 10 , 61 , 27 , 11 , 80 , 26 , 81 , 100 , 61 , 104 , 105 , 106 , 107 , 108 , 109 , 24 , 110 , 40 , 111 , 112 , 28 , 113 , 114 , 115 , 36 , 66 , 116 , 117 , 118 , 76 , 119 , 120 , 121 , 122 , 2 , 13 , 123 , 124 , 58 , 125 , 116 , 126 , 127 , 36 , 66 , 128 , 103 , 7 , 7 , 129 , 33 , 87 , 103 , 26 , 26 , 51 , 130 , 4 , 5 , 51 , 7 , 11 , 80 , 93 , 94 , 8 , 4 , 131 , 33 , 2 , 2 , 6 , 1
      Nature
      multiple sclerosis, GWAS, genetics

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Multiple sclerosis (OMIM 126200) 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 disability. 1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals; 2, 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 risk. 4 Modestly powered Genome-Wide Association Studies (GWAS) 5- 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility. 11 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 9772 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 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 over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

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          Most cited references17

          • Record: found
          • Abstract: found
          • Article: not found

          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            • Record: found
            • Abstract: found
            • Article: not found

            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              • Record: found
              • Abstract: found
              • Article: not found

              Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20.

              (2009)
              To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                1 August 2011
                10 August 2011
                11 February 2012
                : 476
                : 7359
                : 214-219
                Affiliations
                [1 ]University of Cambridge, Department of Clinical Neurosciences, Addenbrooke’s Hospital, BOX 165, Hills Road, Cambridge, CB2 0QQ, UK
                [2 ]Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
                [3 ]Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
                [4 ]Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA
                [5 ]Center for Neurologic Diseases, Department of Neurology, Brigham & Women’s Hospital, Boston, MA 02115, USA
                [6 ]Dept Statistics, University of Oxford, Oxford OX1 3TG, UK
                [7 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
                [8 ]Westmead Millennium Institute, University of Sydney, Australia
                [9 ]Laboratory for Neuroimmunology, Section of Experimental Neurology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
                [10 ]Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark
                [11 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 00290, Finland
                [12 ]INSERM UMR S 975 CRICM, UPMC, Département de neurologie Pitié-Salpêtrière, AP-HP, Paris, France
                [13 ]Department of Neurology, Klinikum Rechts der Isar der Technischen Universität, Ismaninger Strasse 22, 81675 Munich, Germany
                [14 ]Department of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
                [15 ]Max Delbrueck Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
                [16 ]Institute for Neuroimmunology and Clinical MS Research (inims), Centre for Molecular Neurobiology, Falkenried 94, D-20251 Hamburg, Germany
                [17 ]Department of Clinical Pharmacology, University of Oxford, Old Road Campus Research Building , Old Road Campus, Oxford, OX3 7DQ, UK
                [18 ]Queen’s University Belfast, University Road, Belfast, BT7 1NN, Northern Ireland, UK
                [19 ]Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
                [20 ]Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
                [21 ]Department of Neurology, Oslo University Hospital, N-0407 Oslo, Norway
                [22 ]Department of Neurology, University of Oslo, N-0318 Oslo, Norway
                [23 ]Institute of Basal Medical Sciences, University of Oslo, N-0317 Oslo, Norway
                [24 ]Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland
                [25 ]Clinical Neuroinmunology Unit, Multiple Sclerosis Center of Catalonia (CEM-Cat), Vall d’Hebron University Hospital, Barcelona, Spain
                [26 ]Department of Clinical Neurosciences, Centre for Molecular Medicine CMM, L8:04, Karolinska Institutet, Karolinska Hospital, 171 76 Stockholm, Sweden
                [27 ]Keele University Medical School, Stoke-on-Trent, UK
                [28 ]Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Clinical Neurology Research Group, Tamar Science Park, Plymouth, PL6 8BX, UK
                [29 ]Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK
                [30 ]Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7356, USA
                [31 ]Kaiser Permanente Northern California Division of Research, 2000 Broadway, Oakland, CA, 94612, USA
                [32 ]Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden
                [33 ]Department of Neurology, University of California San Francisco, 505 Parnassus Avenue, S-256, San Francisco, CA 94143-0435, USA
                [34 ]Neurological Institute C. Mondino, IRCCS, Pavia, Italy
                [35 ]The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
                [36 ]Center for Applied Genomics, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA
                [37 ]INSERM U 563 et Pôle Neurosciences, Hopital Purpan, Toulouse, France
                [38 ]School of Medicine, Griffith University, Australia
                [39 ]Florey Neuroscience Institutes, University of Melbourne, Victoria, Australia 3010
                [40 ]Royal Melbourne Hospital, Parkville, Victoria, Australia, 3050
                [41 ]Box Hill Hospital, Box Hill 3128, Australia
                [42 ]Department of Medicine, RMH Cluster, University of Melbourne, Victoria, Australia 3010
                [43 ]Multiple Sclerosis Centre, Department of Neurology, Ospedali Civili di Brescia, Brescia, Italy
                [44 ]Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth WA 6009, Australia
                [45 ]Department of Neurosciences, University of Turin, A.O.U. San Giovanni Battista,Turin, Italy
                [46 ]INSERM U535, Univ Paris-Sud, Villejuif, France
                [47 ]University of Newcastle, University Drive, Callaghan NSW 2308, Australia
                [48 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1540 Alcazar St. NOR 4453, Los Angeles, CA 90033
                [49 ]Department of Neurology, Washington University, St Louis MO, USA
                [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
                [51 ]Harvard Medical School, Boston, MA, USA
                [52 ]Center for Human Genetic Research, Massachusetts General Hospital, USA
                [53 ]The UK DNA Banking Network, Centre for Integrated Genomic Medical Research, University of Manchester, UK
                [54 ]Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
                [55 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
                [56 ]Service de Neurologie, Hôpital Central, Nancy, France
                [57 ]National Multiple Sclerosis Center, 1820 Melsbroek, Belgium
                [58 ]Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
                [59 ]Department of Neurology, Tampere University Hospital, Tampere, Finland
                [60 ]University of Tampere, Medical School, Tampere, Finland
                [61 ]Menzies Research Institute, Locked Bag 23, Hobart, Tasmania, Australia 7000
                [62 ]Department of Neurological Sciences, Centro Dino Ferrari, University of Milan, Fondazione Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
                [63 ]Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate (VA), Italy
                [64 ]Service de Neurologie, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France
                [65 ]Belfast Health and Social Care Trust, City Hospital, Belfast BT9 7AB, Northern Ireland,UK
                [66 ]Division of Genetics, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA
                [67 ]Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 Civic Center Blvd., Philadelphia, PA, 19104, USA
                [68 ]Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, Milan, Italy
                [69 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 17177 Stockholm, Sweden
                [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
                [71 ]Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany
                [72 ]Centre National de Genotypage, 2 rue Gaston Cremieux, CO 5721, 91057 Evry Cedex, France
                [73 ]Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany
                [74 ]Clinic for Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Germany
                [75 ]Centre for Neuroscience, University of Melbourne, Victoria, Australia 3010
                [76 ]Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Munich, Germany
                [77 ]Seinäjoki Central Hospital, Seinäjoki, Finland
                [78 ]Hunter Medical Research Institute, John Hunter Hospital, Lookout Road, New Lambton NSW 2305, Australia
                [79 ]SCDU Neurology, Maggiore della Carità Hospital, Novara, Italy
                [80 ]Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, 00290, Finland
                [81 ]Molecular Medicine, Department of Medical Sciences, Uppsala University, Entrance 70, 3rd Floor, Res Dept 2, Univeristy Hospital, S-75185, Uppsala, Sweden
                [82 ]Human Genetics and Cancer Biology, Genome Institute of Singapore, Singapore 138672
                [83 ]Institute of Immunology, Oslo University Hospital, N-0027 Oslo, Norway
                [84 ]Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy
                [85 ]Dept of Psychiatry and Human Behavior, University of California, Irvine (UCI), 5251 California Av, S.te 240, Irvine CA, 92617 - USA
                [86 ]Christchurch School of Medicine, University of Otago, Christchurch, New Zealand
                [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, FL 33136, USA
                [88 ]Greater Manchester Centre for Clinical Neurosciences, Hope Hospital, Salford, UK
                [89 ]The Department of Neurology, Dunedin Public Hospital, Otago, NZ
                [90 ]The Multiple Sclerosis National Competence Centre, Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway
                [91 ]Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway
                [92 ]Plymouth Hospitals NHS Trust, Department of Neurology, Derriford Hospital, Plymouth, PL6 8DH, UK
                [93 ]Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
                [94 ]Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [95 ]Pôle Neurosciences Cliniques,Service de Neurologie, Hôpital de la Timone, Marseille, France
                [96 ]Department Neurology, Oulu University Hospital, Oulu, Finland
                [97 ]UK MS Tissue Bank, Wolfson Neuroscience Laboratories, Imperial College London, Hammersmith Hospital, London, W12 0NN
                [98 ]Université de Montréal & Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada
                [99 ]Neurology and Center for Experimental Neurological Therapy (CENTERS), Sapienza University of Rome, Italy
                [100 ]KOS Genetic Srl, Via Podgora, 7 - 20123 Milan - Italy
                [101 ]Department of General Internal Medicine, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
                [102 ]Systems Biology and Protein-Protein Interaction, Center for Molecular Neurobiology, Falkenried 94, D-20251 Hamburg, Germany
                [103 ]Center for Human Genetics Research, Vanderbilt University Medical Center, 519 Light Hall, Nashville, TN 37232, USA
                [104 ]Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, Western Australia 6008
                [105 ]Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK
                [106 ]Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland
                [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
                [108 ]Service de Neurologie et Faculté de Médecine de Reims, Université de Reims Champagne-Ardenne, Reims, France
                [109 ]University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia
                [110 ]Dept Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
                [111 ]St. Vincent’s University Hospital, Dublin, Ireland
                [112 ]Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Eire
                [113 ]Centre for Gastroenterology, Bart’s and the London School of Medicine and Dentistry, London E1 2AT, UK
                [114 ]Department of Neurosciences, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Spain
                [115 ]Clinical Neurosciences, St George’s University of London, London SW17 0RE
                [116 ]Dept Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London SE1 9RT, UK
                [117 ]Medical Research Council Biostatistics Unit, Robinson Way, Cambridge, CB2 0SR, UK
                [118 ]Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY
                [119 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany
                [120 ]Klinikum Grosshadern, Munich, Germany
                [121 ]King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK
                [122 ]Department of Neurology, Auckland City Hospital, Grafton Road, Auckland, New Zealand
                [123 ]Institut für Humangenetik, Technische Universität München, Germany
                [124 ]Institut für Humangenetik, Helmholtz Zentrum München, Germany
                [125 ]Popgen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
                [126 ]Pôle Recherche et Santé Publique, CHU Pontchaillou, Rennes, France
                [127 ]NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK
                [128 ]Dept Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK
                [129 ]Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE
                [130 ]Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA
                [131 ]Department of Neurology & Immunology, Yale University Medical School, New Haven, CT, USA
                Author notes
                Correspondence and requests for materials should be addressed to D.A.S.C. ( alastair.compston@ 123456medschl.cam.ac.uk ) and P.D. ( donnelly@ 123456well.ox.ac.uk ) on behalf of the IMSGC and WTCCC2 respectively.
                [*]

                A full list of authors appears at the end of this article. Membership of both consortia and details of individual contributions are listed in the Supplementary Material.

                All authors reviewed and approved the manuscript.

                [*]

                These authors contributed equally.

                [†]

                These authors jointly directed the study

                Article
                UKMS36028
                10.1038/nature10251
                3182531
                21833088
                5fbdda5c-cff5-4a36-a2d9-1e4c17af5acb

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                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 085475 || WT
                Funded by: Wellcome Trust :
                Award ID: 085475 || WT
                Funded by: Wellcome Trust :
                Award ID: 085475 || WT
                Funded by: Wellcome Trust :
                Award ID: 084702 || WT
                Funded by: Multiple Sclerosis Society :
                Award ID: 898 || MSS_
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                multiple sclerosis,gwas,genetics
                Uncategorized
                multiple sclerosis, gwas, genetics

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