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.
| Original language | English |
|---|---|
| Pages (from-to) | 214-219 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 476 |
| Issue number | 7359 |
| DOIs | |
| State | Published - 11 Aug 2011 |
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In: Nature, Vol. 476, No. 7359, 11.08.2011, p. 214-219.
Research output: Contribution to journal › Letter › peer-review
TY - JOUR
T1 - Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
AU - Sawcer, Stephen
AU - Hellenthal, Garrett
AU - Pirinen, Matti
AU - Spencer, Chris C.A.
AU - Patsopoulos, Nikolaos A.
AU - Moutsianas, Loukas
AU - Dilthey, Alexander
AU - Su, Zhan
AU - Freeman, Colin
AU - Hunt, Sarah E.
AU - Edkins, Sarah
AU - Gray, Emma
AU - Booth, David R.
AU - Potter, Simon C.
AU - Goris, An
AU - Band, Gavin
AU - Oturai, Annette Bang
AU - Strange, Amy
AU - Saarela, Janna
AU - Bellenguez, Céline
AU - Fontaine, Bertrand
AU - Gillman, Matthew
AU - Hemmer, Bernhard
AU - Gwilliam, Rhian
AU - Zipp, Frauke
AU - Jayakumar, Alagurevathi
AU - Martin, Roland
AU - Leslie, Stephen
AU - Hawkins, Stanley
AU - Giannoulatou, Eleni
AU - D'Alfonso, Sandra
AU - Blackburn, Hannah
AU - Boneschi, Filippo Martinelli
AU - Liddle, Jennifer
AU - Harbo, Hanne F.
AU - Perez, Marc L.
AU - Spurkland, Anne
AU - Waller, Matthew J.
AU - Mycko, Marcin P.
AU - Ricketts, Michelle
AU - Comabella, Manuel
AU - Hammond, Naomi
AU - Kockum, Ingrid
AU - McCann, Owen T.
AU - Ban, Maria
AU - Whittaker, Pamela
AU - Kemppinen, Anu
AU - Weston, Paul
AU - Hawkins, Clive
AU - Widaa, Sara
AU - Zajicek, John
AU - Dronov, Serge
AU - Robertson, Neil
AU - Bumpstead, Suzannah J.
AU - Barcellos, Lisa F.
AU - Ravindrarajah, Rathi
AU - Abraham, Roby
AU - Alfredsson, Lars
AU - Ardlie, Kristin
AU - Aubin, Cristin
AU - Baker, Amie
AU - Baker, Katharine
AU - Baranzini, Sergio E.
AU - Bergamaschi, Laura
AU - Bergamaschi, Roberto
AU - Bernstein, Allan
AU - Berthele, Achim
AU - Boggild, Mike
AU - Bradfield, Jonathan P.
AU - Brassat, David
AU - Broadley, Simon A.
AU - Buck, Dorothea
AU - Butzkueven, Helmut
AU - Capra, Ruggero
AU - Carroll, William M.
AU - Cavalla, Paola
AU - Celius, Elisabeth G.
AU - Cepok, Sabine
AU - Chiavacci, Rosetta
AU - Clerget-Darpoux, Françoise
AU - Clysters, Katleen
AU - Comi, Giancarlo
AU - Cossburn, Mark
AU - Cournu-Rebeix, Isabelle
AU - Cox, Mathew B.
AU - Cozen, Wendy
AU - Cree, Bruce A.C.
AU - Cross, Anne H.
AU - Cusi, Daniele
AU - Daly, Mark J.
AU - Davis, Emma
AU - De Bakker, Paul I.W.
AU - Debouverie, Marc
AU - D'Hooghe, Marie Beatrice
AU - Dixon, Katherine
AU - Dobosi, Rita
AU - Dubois, Bénédicte
AU - Ellinghaus, David
AU - Elovaara, Irina
AU - Esposito, Federica
AU - Fontenille, Claire
AU - Foote, Simon
AU - Franke, Andre
AU - Galimberti, Daniela
AU - Ghezzi, Angelo
AU - Glessner, Joseph
AU - Gomez, Refujia
AU - Gout, Olivier
AU - Graham, Colin
AU - Grant, Struan F.A.
AU - Guerini, Franca Rosa
AU - Hakonarson, Hakon
AU - Hall, Per
AU - Hamsten, Anders
AU - Hartung, Hans Peter
AU - Heard, Rob N.
AU - Heath, Simon
AU - Hobart, Jeremy
AU - Hoshi, Muna
AU - Infante-Duarte, Carmen
AU - Ingram, Gillian
AU - Ingram, Wendy
AU - Islam, Talat
AU - Jagodic, Maja
AU - Kabesch, Michael
AU - Kermode, Allan G.
AU - Kilpatrick, Trevor J.
AU - Kim, Cecilia
AU - Klopp, Norman
AU - Koivisto, Keijo
AU - Larsson, Malin
AU - Lathrop, Mark
AU - Lechner-Scott, Jeannette S.
AU - Leone, Maurizio A.
AU - Leppä, Virpi
AU - Liljedahl, Ulrika
AU - Bomfim, Izaura Lima
AU - Lincoln, Robin R.
AU - Link, Jenny
AU - Liu, Jianjun
AU - Lorentzen, Aslaug R.
AU - Lupoli, Sara
AU - MacCiardi, Fabio
AU - MacK, Thomas
AU - Marriott, Mark
AU - Martinelli, Vittorio
AU - Mason, Deborah
AU - McCauley, Jacob L.
AU - Mentch, Frank
AU - Mero, Inger Lise
AU - Mihalova, Tania
AU - Montalban, Xavier
AU - Mottershead, John
AU - Myhr, Kjell Morten
AU - Naldi, Paola
AU - Ollier, William
AU - Page, Alison
AU - Palotie, Aarno
AU - Pelletier, Jean
AU - Piccio, Laura
AU - Pickersgill, Trevor
AU - Piehl, Fredrik
AU - Pobywajlo, Susan
AU - Quach, Hong L.
AU - Ramsay, Patricia P.
AU - Reunanen, Mauri
AU - Reynolds, Richard
AU - Rioux, John D.
AU - Rodegher, Mariaemma
AU - Roesner, Sabine
AU - Rubio, Justin P.
AU - Rückert, Ina Maria
AU - Salvetti, Marco
AU - Salvi, Erika
AU - Santaniello, Adam
AU - Schaefer, Catherine A.
AU - Schreiber, Stefan
AU - Schulze, Christian
AU - Scott, Rodney J.
AU - Sellebjerg, Finn
AU - Selmaj, Krzysztof W.
AU - Sexton, David
AU - Shen, Ling
AU - Simms-Acuna, Brigid
AU - Skidmore, Sheila
AU - Sleiman, Patrick M.A.
AU - Smestad, Cathrine
AU - Sørensen, Per Soelberg
AU - Søndergaard, Helle Bach
AU - Stankovich, Jim
AU - Strange, Richard C.
AU - Sulonen, Anna Maija
AU - Sundqvist, Emilie
AU - Syvänen, Ann Christine
AU - Taddeo, Francesca
AU - Taylor, Bruce
AU - Blackwell, Jenefer M.
AU - Tienari, Pentti
AU - Bramon, Elvira
AU - Tourbah, Ayman
AU - Brown, Matthew A.
AU - Tronczynska, Ewa
AU - Casas, Juan P.
AU - Tubridy, Niall
AU - Corvin, Aiden
AU - Vickery, Jane
AU - Jankowski, Janusz
AU - Villoslada, Pablo
AU - Markus, Hugh S.
AU - Wang, Kai
AU - Mathew, Christopher G.
AU - Wason, James
AU - Palmer, Colin N.A.
AU - Wichmann, Erich
AU - Plomin, Robert
AU - Willoughby, Ernest
AU - Rautanen, Anna
AU - Winkelmann, Juliane
AU - Wittig, Michael
AU - Trembath, Richard C.
AU - Yaouanq, Jacqueline
AU - Viswanathan, Ananth C.
AU - Zhang, Haitao
AU - Wood, Nicholas W.
AU - Zuvich, Rebecca
AU - Deloukas, Panos
AU - Langford, Cordelia
AU - Duncanson, Audrey
AU - Oksenberg, Jorge R.
AU - Pericak-Vance, Margaret A.
AU - Haines, Jonathan L.
AU - Olsson, Tomas
AU - Hillert, Jan
AU - Ivinson, Adrian J.
AU - De Jager, Philip L.
AU - Peltonen, Leena
AU - Stewart, Graeme J.
AU - Hafler, David A.
AU - Hauser, Stephen L.
AU - McVean, Gil
AU - Donnelly, Peter
AU - Compston, Alastair
N1 - Funding Information: AcknowledgementsThe principalfundingfor thisstudy wasprovidedbythe Wellcome Trust (085475/B/08/Z, 085475/Z/08/Z, 075491/Z/04/Z and 068545/Z/02). The work was also supported by National Institutes of Health (AI076544, NS032830, NS049477, NS19142, NS049510, NS26799, NS43559, NS067305, CA104021, RR020092, RR024992 and K23N/S048869), US National Multiple Sclerosis Society (RG 4201-A-1), Nancy Davis Foundation, Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G0700061, G0000934), Multiple Sclerosis Society of Great Britain and Northern Ireland (898/08), Wolfson Royal Society Merit Award, Peter Doherty fellowship, Lagrange Fellowship, Harry Weaver Neuroscience Scholarships, Australian National Health and Medical Research Council (NHMRC), Australian Research Council Linkage Program Grant, JHH Charitable Trust Fund, Multiple Sclerosis Research Australia, Health Research Council New Zealand, National MS Society of New Zealand, Wetenschappelijk Onderzoek Multiple Sclerose, Bayer Chair on Fundamental Genetic Research regarding the Neuroimmunological Aspects of Multiple Sclerosis, Biogen Idec Chair Translational Research in Multiple Sclerosis, FWO-Vlaanderen, Belgian Neurological Society, Danish Multiple Sclerosis Society, Neuropromise EU grant (LSHM-CT-2005-018637), Center of Excellence for Disease Genetics of the Academy of Finland, Sigrid Juselius Foundation, Helsinki University Central Hospital Research Foundation, Bundesministerium für Bildung und Technologie (KKNMS consortium Control MS), Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche sur la Sclérose En Plaques (ARSEP), Association Française contre les Myopathies (AFM), Italian Foundation for Multiple Sclerosis (FISM grants 2002/R/40, 2005/R/10, 2008/R/11 and 2008/R/15), Italian Ministry of Health (grant Giovani Ricercatori 2007 - D.lgs 502/92), Regione Piemonte (grants 2003, 2004, 2008, 2009), CRT Foundation, Turin, Moorfields/UCL Institute of Ophthalmology NIHR Biomedical Research Centre, Norwegian MS Register and Biobank, Research Council of Norway, South-Eastern and Western Norway regional Health Authories, Ullevål University Hospital Scientific Advisory Council, Haukeland University Hospital, Amici Centro Sclerosi Multipla del San Raffaele (ACESM), Association of British Neurologists, SpanishMinistryof Health(FISPI060117), Bibbi andNiels JensensFoundation, Montel Williams foundation, Hjärnfonden and Swedish medical research council (8691), Stockholm County Council (562183), Swedish Council for Working life and Social Research, Gemeinnützige Hertie Stiftung, Northern California Kaiser Permanente members and Polpharma Foundation, and Washington University Institute of Clinical and Translational Sciences—Brain, Behavioral and Performance Unit. We acknowledge use of data from the British 1958 Birth Cohort, the UK National Blood Service,the popgenbiobank, the KORAandMONICAAugsburgstudies,the Accelerated Cure Project, the Brigham & Women’s Hospital PhenoGenetic Project, the Swedish CAD project, the Norwegian Bone Marrow Donor Registry, the Children’s Hospital of Philadelphia (CHOP), the Swedish Breast Cancer study, BRC-REFGENSEP (Pitié-Salpêtrière Centre d’Investigation Clinique (CIC) and Généthon) and HYPERGENES (HEALTH-F4-2007-201550). Projects received support from the German Ministry of Education and Research, the Helmholtz Zentrum München— National Research Center, the German National Genome Research Network (NGFN), the LMUinnovativ, the Knut and Alice Wallenberg Foundation, the Center for Applied Genomics from the Children’s Hospital of Philadelphia Development Award, the Agency for Science & Technology and Research of Singapore, and the Susan G. Komen Breast Cancer Foundation. We thank S. Bertrand, J. Bryant, S. L. Clark, L. Collimedaglia,
PY - 2011/8/11
Y1 - 2011/8/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/80051684615
U2 - 10.1038/nature10251
DO - 10.1038/nature10251
M3 - Letter
C2 - 21833088
AN - SCOPUS:80051684615
SN - 0028-0836
VL - 476
SP - 214
EP - 219
JO - Nature
JF - Nature
IS - 7359
ER -