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

Item Type:	Article
Title:	Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Creators Name:	Sawcer, S. and Hellenthal, G. and Pirinen, M. and Spencer, C.C. and Patsopoulos, N.A. and Moutsianas, L. and Dilthey, A. and Su, Z. and Freeman, C. and Hunt, S.E. and Edkins, S. and Gray, E. and Booth, D.R. and Potter, S.C. and Goris, A. and Band, G. and Oturai, A.B. and Strange, A. and Saarela, J. and Bellenguez, C. and Fontaine, B. and Gillman, M. and Hemmer, B. and Gwilliam, R. and Zipp, F. and Jayakumar, A. and Martin, R. and Leslie, S. and Hawkins, S. and Giannoulatou, E. and D'alfonso, S. and Blackburn, H. and Boneschi, F.M. and Liddle, J. and Harbo, H.F. and Perez, M.L. and Spurkland, A. and Waller, M.J. and Mycko, M.P. and Ricketts, M. and Comabella, M. and Hammond, N. and Kockum, I. and McCann, O.T. and Ban, M. and Whittaker, P. and Kemppinen, A. and Weston, P. and Hawkins, C. and Widaa, S. and Zajicek, J. and Dronov, S. and Robertson, N. and Bumpstead, S.J. and Barcellos, L.F. and Ravindrarajah, R. and Abraham, R. and Alfredsson, L. and Ardlie, K. and Aubin, C. and Baker, A. and Baker, K. and Baranzini, S.E. and Bergamaschi, L. and Bergamaschi, R. and Bernstein, A. and Berthele, A. and Boggild, M. and Bradfield, J.P. and Brassat, D. and Broadley, S.A. and Buck, D. and Butzkueven, H. and Capra, R. and Carroll, W.M. and Cavalla, P. and Celius, E.G. and Cepok, S. and Chiavacci, R. and Clerget-Darpoux, F. and Clysters, K. and Comi, G. and Cossburn, M. and Cournu-Rebeix, I. and Cox, M.B. and Cozen, W. and Cree, B.A. and Cross, A.H. and Cusi, D. and Daly, M.J. and Davis, E. and de Bakker, P.I. and Debouverie, M. and D'hooghe, M.B. and Dixon, K. and Dobosi, R. and Dubois, B. and Ellinghaus, D. and Elovaara, I. and Esposito, F. and Fontenille, C. and Foote, S. and Franke, A. and Galimberti, D. and Ghezzi, A. and Glessner, J. and Gomez, R. and Gout, O. and Graham, C. and Grant, S.F. and Guerini, F.R. and Hakonarson, H. and Hall, P. and Hamsten, A. and Hartung, H.P. and Heard, R.N. and Heath, S. and Hobart, J. and Hoshi, M. and Infante-Duarte, C. and Ingram, G. and Ingram, W. and Islam, T. and Jagodic, M. and Kabesch, M. and Kermode, A.G. and Kilpatrick, T.J. and Kim, C. and Klopp, N. and Koivisto, K. and Larsson, M. and Lathrop, M. and Lechner-Scott, J.S. and Leone, M.A. and Leppa, V. and Liljedahl, U. and Bomfim, I.L. and Lincoln, R.R. and Link, J. and Liu, J. and Lorentzen, A.R. and Lupoli, S. and Macciardi, F. and Mack, T. and Marriott, M. and Martinelli, V. and Mason, D. and McCauley, J.L. and Mentch, F. and Mero, I.L. and Mihalova, T. and Montalban, X. and Mottershead, J. and Myhr, K.M. and Naldi, P. and Ollier, W. and Page, A. and Palotie, A. and Pelletier, J. and Piccio, L. and Pickersgill, T. and Piehl, F. and Pobywajlo, S. and Quach, H.L. and Ramsay, P.P. and Reunanen, M. and Reynolds, R. and Rioux, J.D. and Rodegher, M. and Roesner, S. and Rubio, J.P. and Ruckert, I.M. and Salvetti, M. and Salvi, E. and Santaniello, A. and Schaefer, C.A. and Schreiber, S. and Schulze, C. and Scott, R.J. and Sellebjerg, F. and Selmaj, K.W. and Sexton, D. and Shen, L. and Simms-Acuna, B. and Skidmore, S. and Sleiman, P.M. and Smestad, C. and Sorensen, P.S. and Sondergaard, H.B. and Stankovich, J. and Strange, R.C. and Sulonen, A.M. and Sundqvist, E. and Syvanen, A.C. and Taddeo, F. and Taylor, B. and Blackwell, J.M. and Tienari, P. and Bramon, E. and Tourbah, A. and Brown, M.A. and Tronczynska, E. and Casas, J.P. and Tubridy, N. and Corvin, A. and Vickery, J. and Jankowski, J. and Villoslada, P. and Markus, H.S. and Wang, K. and Mathew, C.G. and Wason, J. and Palmer, C.N. and Wichmann, H.E. and Plomin, R. and Willoughby, E. and Rautanen, A. and Winkelmann, J. and Wittig, M. and Trembath, R.C. and Yaouanq, J. and Viswanathan, A.C. and Zhang, H. and Wood, N.W. and Zuvich, R. and Deloukas, P. and Langford, C. and Duncanson, A. and Oksenberg, J.R. and Pericak-Vance, M.A. and Haines, J.L. and Olsson, T. and Hillert, J. and Ivinson, A.J. and De Jager, P.L. and Peltonen, L. and Stewart, G.J. and Hafler, D.A. and Hauser, S.L. and McVean, G. and Donnelly, P. and Compston, A.
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 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. 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.
Keywords:	Alleles, Cell Differentiation, Cellular Immunity, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Helper-Inducer T-Lymphocytes, HLA-A Antigens, HLA-DR Antigens, Human Genome, Major Histocompatibility Complex, Multiple Sclerosis, Sample Size, Single Nucleotide Polymorphism
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	476
Number:	7359
Page Range:	214-219
Date:	10 August 2011
Official Publication:	https://doi.org/10.1038/nature10251
PubMed:	View item in PubMed

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