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

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., 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., Boneschi, F. M., Liddle, J., Harbo, H. F., Perez, M. L., Spurkland, A., Waller, M. J., Mycko, M. P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O. T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S. J., Barcellos, L. F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S. E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J. P., Brassat, D., Broadley, S. A., Buck, D., Butzkueven, H., Capra, R., Carroll, W. M., Cavalla, P., Celius, E. G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M. B., Cozen, W., Cree, B. A. C., Cross, A. H., Cusi, D., Daly, M. J., Davis, E., De Bakker, P. I. W., Debouverie, M., D'Hooghe, M. B., 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, S. F. A., Guerini, F. R., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H. P., Heard, R. N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A. G., Kilpatrick, T. J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J. S., Leone, M. A., Leppä, V., Liljedahl, U., Bomfim, I. L., Lincoln, R. R., Link, J., Liu, J., Lorentzen, A. R., Lupoli, S., MacCiardi, F., MacK, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J. L., Mentch, F., Mero, I. L., Mihalova, T., Montalban, X., Mottershead, J., Myhr, K. M., Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H. L., Ramsay, P. P., Reunanen, M., Reynolds, R., Rioux, J. D., Rodegher, M., Roesner, S., Rubio, J. P., Rückert, I. M., Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C. A., Schreiber, S., Schulze, C., Scott, R. J., Sellebjerg, F., Selmaj, K. W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P. M. A., Smestad, C., Sørensen, P. S., Søndergaard, H. B., Stankovich, J., Strange, R. C., Sulonen, A. M., Sundqvist, E., Syvänen, A. C., Taddeo, F., Taylor, B., Blackwell, J. M., Tienari, P., Bramon, E., Tourbah, A., Brown, M. A., Tronczynska, E., Casas, J. P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H. S., Wang, K., Mathew, C. G., Wason, J., Palmer, C. N. A., Wichmann, E., Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R. C., Yaouanq, J., Viswanathan, A. C., Zhang, H., Wood, N. W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J. R., Pericak-Vance, M. A., Haines, J. L., Olsson, T., Hillert, J., Ivinson, A. J., De Jager, P. L., Peltonen, L., Stewart, G. J., Hafler, D. A., Hauser, S. L., McVean, G., Donnelly, P., & Compston, A. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature, 476(7359), pp. 214-219.

View at publisher


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. © 2011 Macmillan Publishers Limited. All rights reserved.

Impact and interest:

966 citations in Scopus
Search Google Scholar™
897 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 89357
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :789
Export Date: 21 September 2015
Correspondence Address: Donnelly, P.; Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX 37BN, United Kingdom; email:
Keywords: HLA A antigen, HLA DR antigen, major histocompatibility antigen, allele, antigen presenting cell, cellular immunity, controlled study, gene linkage disequilibrium, gene locus, gene replication, genetic association, genetic risk, genetic susceptibility, genetic variability, helper cell, human, letter, lymphocyte differentiation, major clinical study, multiple sclerosis, pathogenesis, priority journal, single nucleotide polymorphism, Alleles, Cell Differentiation, Europe, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, HLA-A Antigens, HLA-DR Antigens, Humans, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Sample Size, T-Lymphocytes, Helper-Inducer
DOI: 10.1038/nature10251
ISSN: 0028-0836
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © 2011 Macmillan Publishers Limited
Deposited On: 21 Oct 2015 02:31
Last Modified: 26 Feb 2016 05:03

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page