Journal article

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

Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris CA 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, Celine Bellenguez Show all

NATURE | NATURE PUBLISHING GROUP | Published : 2011

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 disability. 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, 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. Modestly powered genome-wide association studies (GWAS) have enab..

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Grants

Awarded by Wellcome Trust


Awarded by National Institutes of Health


Awarded by US National Multiple Sclerosis Society


Awarded by UK Medical Research Council


Awarded by Multiple Sclerosis Society of Great Britain and Northern Ireland


Awarded by Neuropromise EU


Awarded by Italian Foundation for Multiple Sclerosis


Awarded by Italian Ministry of Health


Awarded by Regione Piemonte


Awarded by Spanish Ministry of Health


Awarded by Hjarnfonden and Swedish medical research council


Awarded by Stockholm County Council


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES


Awarded by NATIONAL CENTER FOR RESEARCH RESOURCES


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Awarded by Medical Research Council


Awarded by National Institute for Health Research


Awarded by Parkinson"s UK


Funding 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 fur Bildung und Technologie (KKNMS consortium Control MS), Deutsche Forschungsgemeinschaft, Institut National de la Sante et de la Recherche Medicale (INSERM), Association pour la Recherche sur la Sclerose En Plaques (ARSEP), Association Francaise 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, Ulleval 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, Hjarnfonden and Swedish medical research council (8691), Stockholm County Council (562183), Swedish Council for Working life and Social Research, Gemeinnutzige 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 (Pitie-Salpetriere Centre d'Investigation Clinique (CIC) and Genethon) and HYPERGENES (HEALTH-F4-2007-201550).Projects received support from the German Ministry of Education and Research, the Helmholtz Zentrum Munchen-National Research Center, the German National Genome Research Network (NGFN), the LMUinnovativ, the Knut and Alice Wallenberg Foundation, the Cener 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.