Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
Citation:
Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, S?rensen PS, S?ndergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis., Nature, 476, 7359, 2011, 214-9Download Item:
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.
Author's Homepage:
http://people.tcd.ie/acorvinDescription:
PUBLISHED
Author: CORVIN, AIDEN PETER
Type of material:
Journal ArticleCollections
Series/Report no:
Nature;476;
7359;
Availability:
Full text availableKeywords:
multiple sclerosis; GWAS; geneticsMetadata
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