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

Stephen J Sawcer, Garrett Hellenthal, Matti Pirinen, Chris Spencer, Nikolaos A Patsopoulos, Loukas Moutsianas, Alexander T Dilthey, Zhan Su, Colin Freeman, Sarah E Hunt, Sarah Edkins, Emma Gray, David R Booth, Simon C Potter, An Goris, Gavin Band, Annette Oturai, Amy Strange, Janna Saarela, Celine BellenguezBertrand Fontaine, Matthew Gillman, Bernhard Hemmer, Rhian Gwilliam, Frauke Zipp, Alagurevathi Jayakumar, Roland M Martin, Stephen Leslie, Stanley Arthur Hawkins, Eleni Giannoulatou, Sandra D'Alfonso, Hannah Blackburn, Filippo Martinelli-Boneschi, Jennifer Liddle, Hanne F Harbo, Marc L Perez, Anne Spurkland, Matthew Waller, Marcin P Mycko, Michelle Ricketts, Manuel Comabella, Naomi Hammond, Ingrid Kockum, Owen T McCann, Maria Ban, Pamela Whittaker, Anu Kemppinen, Paul Weston, Clive Hawkins, Helmut Butzkueven

Research output: Contribution to journalArticleResearchpeer-review

2118 Citations (Scopus)


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 genomewide 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 HLADRB1 risk alleles and confirmed that variation in the HLAA 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 Thelpercell differentiation in the pathogenesis of multiple sclerosis. (c) 2011 Macmillan Publishers Limited. All rights reserved.
Original languageEnglish
Pages (from-to)214 - 219
Number of pages6
Issue number7359
Publication statusPublished - 2011

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