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


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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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.

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Correspondence to Peter Donnelly or Alastair Compston.

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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)

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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).

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