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

Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C. A. 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 BellenguezBertrand Fontaine, Matthew Gillman, Bernhard Hemmer, Rhian Gwilliam, Frauke Zipp, Alagurevathi Jayakumar, Roland Martin, Stephen Leslie, Stanley Hawkins, Eleni Giannoulatou, Sandra D'alfonso, Hannah Blackburn, Filippo Martinelli Boneschi, Jennifer Liddle, Hanne F. Harbo, Marc L. Perez, Anne Spurkland, Matthew J. 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, Colin N. A. Palmer, Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co

    Research output: Contribution to journalLetter

    1704 Citations (Scopus)

    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(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.

    Original languageEnglish
    Pages (from-to)214-219
    Number of pages6
    JournalNature
    Volume476
    Issue number7359
    DOIs
    Publication statusPublished - 11 Aug 2011

    Keywords

    • GENOME-WIDE ASSOCIATION
    • SUSCEPTIBILITY LOCI
    • HETEROGENEITY
    • HAPLOTYPES
    • VARIANTS
    • ALLELES

    Cite this

    Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C. A., Patsopoulos, N. A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S. E., Edkins, S., Gray, E., Booth, D. R., Potter, S. C., Goris, A., Band, G., Oturai, A. B., Strange, A., Saarela, J., ... Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 476(7359), 214-219. https://doi.org/10.1038/nature10251