期刊
NATURE
卷 476, 期 7359, 页码 214-219出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10251
关键词
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资金
- Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 075491/Z/04/Z, 068545/Z/02]
- National Institutes of Health [AI076544, NS032830, NS049477, NS19142, NS049510, NS26799, NS43559, NS067305, CA104021, RR020092, RR024992, 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
- Peter Doherty fellowship
- Lagrange Fellowship
- Harry Weaver Neuroscience Scholarships
- Australian National Health and Medical Research Council (NHMRC)
- Australian Research Council
- JHH Charitable Trust
- 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
- Biogen Idec Chair Translational Research in Multiple Sclerosis
- FWO-Vlaanderen
- Belgian Neurological Society
- Danish Multiple Sclerosis Society
- Neuropromise EU [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 [2002/R/40, 2005/R/10, 2008/R/11, 2008/R/15]
- Italian Ministry of Health [Giovani Ricercatori 2007-D.lgs 502/92]
- Regione Piemonte [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
- Washington University Institute of Clinical and Translational Sciences-Brain, Behavioral and Performance Unit
- German Ministry of Education and Research
- Helmholtz Zentrum Munchen-National Research Center
- German National Genome Research Network (NGFN)
- LMUinnovativ
- Knut and Alice Wallenberg Foundation
- Children's Hospital of Philadelphia
- Agency for Science & Technology and Research of Singapore
- Susan G. Komen Breast Cancer Foundation
- Medical Research Council [G0700061, G0100594, G0901461, G19/2, G9817803B, G0901310, G0400017, MC_EX_G0800860, G0801418B] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379, PDA/02/06/016] Funding Source: researchfish
- Parkinson's UK [J-0804] Funding Source: researchfish
- MRC [G0901310, G0901461, G0100594, G19/2, MC_EX_G0800860, G0700061, G0400017] Funding Source: UKRI
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(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 have 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 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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