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; Céline Bellenguez; Bertrand 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; Sara Widaa; John Zajicek; Serge Dronov; Neil Robertson; Suzannah J. Bumpstead; Lisa F. Barcellos; Rathi Ravindrarajah; Roby Abraham; Lars Alfredsson; Kristin Ardlie; Cristin Aubin; Amie Baker; Katharine Baker; Sergio E. Baranzini; Laura Bergamaschi; Roberto Bergamaschi; Allan Bernstein; Achim Berthele; Mike Boggild; Jonathan P. Bradfield; David Brassat; Simon A. Broadley; Dorothea Buck; Helmut Butzkueven; Ruggero Capra; William M. Carroll; Paola Cavalla; Elisabeth G. Celius; Sabine Cepok; Rosetta Chiavacci; Françoise Clerget-Darpoux; Katleen Clysters; Giancarlo Comi; Mark Cossburn; Isabelle Cournu-Rebeix; Mathew B. Cox; Wendy Cozen; Bruce A.C. Cree; Anne H. Cross; Daniele Cusi; Mark J. Daly; Emma Davis; Paul I.W. De Bakker; Marc Debouverie; Marie Beatrice D'Hooghe; Katherine Dixon; Rita Dobosi; Bénédicte Dubois; David Ellinghaus; Irina Elovaara; Federica Esposito; Claire Fontenille; Simon Foote; Andre Franke; Daniela Galimberti; Angelo Ghezzi; Joseph Glessner; Refujia Gomez; Olivier Gout; Colin Graham; Struan F.A. Grant; Franca Rosa Guerini; Hakon Hakonarson; Per Hall; Anders Hamsten; Hans Peter Hartung; Rob N. Heard; Simon Heath; Jeremy Hobart; Muna Hoshi; Carmen Infante-Duarte; Gillian Ingram; Wendy Ingram; Talat Islam; Maja Jagodic; Michael Kabesch; Allan G. Kermode; Trevor J. Kilpatrick; Cecilia Kim; Norman Klopp; Keijo Koivisto; Malin Larsson; Mark Lathrop; Jeannette S. Lechner-Scott; Maurizio A. Leone; Virpi Leppä; Ulrika Liljedahl; Izaura Lima Bomfim; Robin R. Lincoln; Jenny Link; Jianjun Liu; Aslaug R. Lorentzen; Sara Lupoli; Fabio MacCiardi; Thomas MacK; Mark Marriott; Vittorio Martinelli; Deborah Mason; Jacob L. McCauley; Frank Mentch; Inger Lise Mero; Tania Mihalova; Xavier Montalban; John Mottershead; Kjell Morten Myhr; Paola Naldi; William Ollier; Alison Page; Aarno Palotie; Jean Pelletier; Laura Piccio; Trevor Pickersgill; Fredrik Piehl; Susan Pobywajlo; Hong L. Quach; Patricia P. Ramsay; Mauri Reunanen; Richard Reynolds; John D. Rioux; Mariaemma Rodegher; Sabine Roesner; Justin P. Rubio; Ina Maria Rückert; Marco Salvetti; Erika Salvi; Adam Santaniello; Catherine A. Schaefer; Stefan Schreiber; Christian Schulze; Rodney J. Scott; Finn Sellebjerg; Krzysztof W. Selmaj; David Sexton; Ling Shen; Brigid Simms-Acuna; Sheila Skidmore; Patrick M.A. Sleiman; Cathrine Smestad; Per Soelberg Sørensen; Helle Bach Søndergaard; Jim Stankovich; Richard C. Strange; Anna Maija Sulonen; Emilie Sundqvist; Ann Christine Syvänen; Francesca Taddeo; Bruce Taylor; Jenefer M. Blackwell; Pentti Tienari; Elvira Bramon; Ayman Tourbah; Matthew A. Brown; Ewa Tronczynska; Juan P. Casas; Niall Tubridy; Aiden Corvin; Jane Vickery; Janusz Jankowski; Pablo Villoslada; Hugh S. Markus; Kai Wang; Christopher G. Mathew; James Wason; Colin N.A. Palmer; Erich Wichmann; Robert Plomin; Ernest Willoughby; Anna Rautanen; Juliane Winkelmann; Michael Wittig; Richard C. Trembath; Jacqueline Yaouanq; Ananth C. Viswanathan; Haitao Zhang; Nicholas W. Wood; Rebecca Zuvich; Panos Deloukas; Cordelia Langford; Audrey Duncanson; Jorge R. Oksenberg; Margaret A. Pericak-Vance; Jonathan L. Haines; Tomas Olsson; Jan Hillert; Adrian J. Ivinson; Philip L. De Jager; Leena Peltonen; Graeme J. Stewart; David A. Hafler; Stephen L. Hauser; Gil McVean; Peter Donnelly; Alastair Compston

doi:10.1038/nature10251

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, Céline 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, Sara Widaa, John Zajicek, Serge Dronov, Neil Robertson, Suzannah J. Bumpstead, Lisa F. Barcellos, Rathi Ravindrarajah, Roby Abraham, Lars Alfredsson, Kristin Ardlie, Cristin Aubin, Amie Baker, Katharine Baker, Sergio E. Baranzini, Laura Bergamaschi, Roberto Bergamaschi, Allan Bernstein, Achim Berthele, Mike Boggild, Jonathan P. Bradfield, David Brassat, Simon A. Broadley, Dorothea Buck, Helmut Butzkueven, Ruggero Capra, William M. Carroll, Paola Cavalla, Elisabeth G. Celius, Sabine Cepok, Rosetta Chiavacci, Françoise Clerget-Darpoux, Katleen Clysters, Giancarlo Comi, Mark Cossburn, Isabelle Cournu-Rebeix, Mathew B. Cox, Wendy Cozen, Bruce A.C. Cree, Anne H. Cross, Daniele Cusi, Mark J. Daly, Emma Davis, Paul I.W. De Bakker, Marc Debouverie, Marie Beatrice D'Hooghe, Katherine Dixon, Rita Dobosi, Bénédicte Dubois, David Ellinghaus, Irina Elovaara, Federica Esposito, Claire Fontenille, Simon Foote, Andre Franke, Daniela Galimberti, Angelo Ghezzi, Joseph Glessner, Refujia Gomez, Olivier Gout, Colin Graham, Struan F.A. Grant, Franca Rosa Guerini, Hakon Hakonarson, Per Hall, Anders Hamsten, Hans Peter Hartung, Rob N. Heard, Simon Heath, Jeremy Hobart, Muna Hoshi, Carmen Infante-Duarte, Gillian Ingram, Wendy Ingram, Talat Islam, Maja Jagodic, Michael Kabesch, Allan G. Kermode, Trevor J. Kilpatrick, Cecilia Kim, Norman Klopp, Keijo Koivisto, Malin Larsson, Mark Lathrop, Jeannette S. Lechner-Scott, Maurizio A. Leone, Virpi Leppä, Ulrika Liljedahl, Izaura Lima Bomfim, Robin R. Lincoln, Jenny Link, Jianjun Liu, Aslaug R. Lorentzen, Sara Lupoli, Fabio MacCiardi, Thomas MacK, Mark Marriott, Vittorio Martinelli, Deborah Mason, Jacob L. McCauley, Frank Mentch, Inger Lise Mero, Tania Mihalova, Xavier Montalban, John Mottershead, Kjell Morten Myhr, Paola Naldi, William Ollier, Alison Page, Aarno Palotie, Jean Pelletier, Laura Piccio, Trevor Pickersgill, Fredrik Piehl, Susan Pobywajlo, Hong L. Quach, Patricia P. Ramsay, Mauri Reunanen, Richard Reynolds, John D. Rioux, Mariaemma Rodegher, Sabine Roesner, Justin P. Rubio, Ina Maria Rückert, Marco Salvetti, Erika Salvi, Adam Santaniello, Catherine A. Schaefer, Stefan Schreiber, Christian Schulze, Rodney J. Scott, Finn Sellebjerg, Krzysztof W. Selmaj, David Sexton, Ling Shen, Brigid Simms-Acuna, Sheila Skidmore, Patrick M.A. Sleiman, Cathrine Smestad, Per Soelberg Sørensen, Helle Bach Søndergaard, Jim Stankovich, Richard C. Strange, Anna Maija Sulonen, Emilie Sundqvist, Ann Christine Syvänen, Francesca Taddeo, Bruce Taylor, Jenefer M. Blackwell, Pentti Tienari, Elvira Bramon, Ayman Tourbah, Matthew A. Brown, Ewa Tronczynska, Juan P. Casas, Niall Tubridy, Aiden Corvin, Jane Vickery, Janusz Jankowski, Pablo Villoslada, Hugh S. Markus, Kai Wang, Christopher G. Mathew, James Wason, Colin N.A. Palmer, Erich Wichmann, Robert Plomin, Ernest Willoughby, Anna Rautanen, Juliane Winkelmann, Michael Wittig, Richard C. Trembath, Jacqueline Yaouanq, Ananth C. Viswanathan, Haitao Zhang, Nicholas W. Wood, Rebecca Zuvich, Panos Deloukas, Cordelia Langford, Audrey Duncanson, Jorge R. Oksenberg, Margaret A. Pericak-Vance, Jonathan L. Haines, Tomas Olsson, Jan Hillert, Adrian J. Ivinson, Philip L. De Jager, Leena Peltonen, Graeme J. Stewart, David A. Hafler, Stephen L. Hauser, Gil McVean, Peter Donnelly, Alastair Compston

Research output: Contribution to journal › Letter › peer-review

2224 Scopus citations

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	https://doi.org/10.1038/nature10251
State	Published - Aug 11 2011

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10.1038/nature10251

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., ... Compston, A. (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

@article{22d08156603f4cacb9cb57a2aacd71e4,

title = "Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis",

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.",

author = "Stephen Sawcer and Garrett Hellenthal and Matti Pirinen and Spencer, {Chris C.A.} and Patsopoulos, {Nikolaos A.} and Loukas Moutsianas and Alexander Dilthey and Zhan Su and Colin Freeman and Hunt, {Sarah E.} and Sarah Edkins and Emma Gray and Booth, {David R.} and Potter, {Simon C.} and An Goris and Gavin Band and Oturai, {Annette Bang} and Amy Strange and Janna Saarela and C{\'e}line Bellenguez and Bertrand Fontaine and Matthew Gillman and Bernhard Hemmer and Rhian Gwilliam and Frauke Zipp and Alagurevathi Jayakumar and Roland Martin and Stephen Leslie and Stanley Hawkins and Eleni Giannoulatou and Sandra D'Alfonso and Hannah Blackburn and Boneschi, {Filippo Martinelli} and Jennifer Liddle and Harbo, {Hanne F.} and Perez, {Marc L.} and Anne Spurkland and Waller, {Matthew J.} and Mycko, {Marcin P.} and Michelle Ricketts and Manuel Comabella and Naomi Hammond and Ingrid Kockum and McCann, {Owen T.} and Maria Ban and Pamela Whittaker and Anu Kemppinen and Paul Weston and Clive Hawkins and Sara Widaa and John Zajicek and Serge Dronov and Neil Robertson and Bumpstead, {Suzannah J.} and Barcellos, {Lisa F.} and Rathi Ravindrarajah and Roby Abraham and Lars Alfredsson and Kristin Ardlie and Cristin Aubin and Amie Baker and Katharine Baker and Baranzini, {Sergio E.} and Laura Bergamaschi and Roberto Bergamaschi and Allan Bernstein and Achim Berthele and Mike Boggild and Bradfield, {Jonathan P.} and David Brassat and Broadley, {Simon A.} and Dorothea Buck and Helmut Butzkueven and Ruggero Capra and Carroll, {William M.} and Paola Cavalla and Celius, {Elisabeth G.} and Sabine Cepok and Rosetta Chiavacci and Fran{\c c}oise Clerget-Darpoux and Katleen Clysters and Giancarlo Comi and Mark Cossburn and Isabelle Cournu-Rebeix and Cox, {Mathew B.} and Wendy Cozen and Cree, {Bruce A.C.} and Cross, {Anne H.} and Daniele Cusi and Daly, {Mark J.} and Emma Davis and {De Bakker}, {Paul I.W.} and Marc Debouverie and D'Hooghe, {Marie Beatrice} and Katherine Dixon and Rita Dobosi and B{\'e}n{\'e}dicte Dubois and David Ellinghaus and Irina Elovaara and Federica Esposito and Claire Fontenille and Simon Foote and Andre Franke and Daniela Galimberti and Angelo Ghezzi and Joseph Glessner and Refujia Gomez and Olivier Gout and Colin Graham and Grant, {Struan F.A.} and Guerini, {Franca Rosa} and Hakon Hakonarson and Per Hall and Anders Hamsten and Hartung, {Hans Peter} and Heard, {Rob N.} and Simon Heath and Jeremy Hobart and Muna Hoshi and Carmen Infante-Duarte and Gillian Ingram and Wendy Ingram and Talat Islam and Maja Jagodic and Michael Kabesch and Kermode, {Allan G.} and Kilpatrick, {Trevor J.} and Cecilia Kim and Norman Klopp and Keijo Koivisto and Malin Larsson and Mark Lathrop and Lechner-Scott, {Jeannette S.} and Leone, {Maurizio A.} and Virpi Lepp{\"a} and Ulrika Liljedahl and Bomfim, {Izaura Lima} and Lincoln, {Robin R.} and Jenny Link and Jianjun Liu and Lorentzen, {Aslaug R.} and Sara Lupoli and Fabio MacCiardi and Thomas MacK and Mark Marriott and Vittorio Martinelli and Deborah Mason and McCauley, {Jacob L.} and Frank Mentch and Mero, {Inger Lise} and Tania Mihalova and Xavier Montalban and John Mottershead and Myhr, {Kjell Morten} and Paola Naldi and William Ollier and Alison Page and Aarno Palotie and Jean Pelletier and Laura Piccio and Trevor Pickersgill and Fredrik Piehl and Susan Pobywajlo and Quach, {Hong L.} and Ramsay, {Patricia P.} and Mauri Reunanen and Richard Reynolds and Rioux, {John D.} and Mariaemma Rodegher and Sabine Roesner and Rubio, {Justin P.} and R{\"u}ckert, {Ina Maria} and Marco Salvetti and Erika Salvi and Adam Santaniello and Schaefer, {Catherine A.} and Stefan Schreiber and Christian Schulze and Scott, {Rodney J.} and Finn Sellebjerg and Selmaj, {Krzysztof W.} and David Sexton and Ling Shen and Brigid Simms-Acuna and Sheila Skidmore and Sleiman, {Patrick M.A.} and Cathrine Smestad and S{\o}rensen, {Per Soelberg} and S{\o}ndergaard, {Helle Bach} and Jim Stankovich and Strange, {Richard C.} and Sulonen, {Anna Maija} and Emilie Sundqvist and Syv{\"a}nen, {Ann Christine} and Francesca Taddeo and Bruce Taylor and Blackwell, {Jenefer M.} and Pentti Tienari and Elvira Bramon and Ayman Tourbah and Brown, {Matthew A.} and Ewa Tronczynska and Casas, {Juan P.} and Niall Tubridy and Aiden Corvin and Jane Vickery and Janusz Jankowski and Pablo Villoslada and Markus, {Hugh S.} and Kai Wang and Mathew, {Christopher G.} and James Wason and Palmer, {Colin N.A.} and Erich Wichmann and Robert Plomin and Ernest Willoughby and Anna Rautanen and Juliane Winkelmann and Michael Wittig and Trembath, {Richard C.} and Jacqueline Yaouanq and Viswanathan, {Ananth C.} and Haitao Zhang and Wood, {Nicholas W.} and Rebecca Zuvich and Panos Deloukas and Cordelia Langford and Audrey Duncanson and Oksenberg, {Jorge R.} and Pericak-Vance, {Margaret A.} and Haines, {Jonathan L.} and Tomas Olsson and Jan Hillert and Ivinson, {Adrian J.} and {De Jager}, {Philip L.} and Leena Peltonen and Stewart, {Graeme J.} and Hafler, {David A.} and Hauser, {Stephen L.} and Gil McVean and Peter Donnelly and Alastair Compston",

note = "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 f{\"u}r Bildung und Technologie (KKNMS consortium Control MS), Deutsche Forschungsgemeinschaft, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), Association pour la Recherche sur la Scl{\'e}rose En Plaques (ARSEP), Association Fran{\c c}aise 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, Ullev{\aa}l 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, Hj{\"a}rnfonden and Swedish medical research council (8691), Stockholm County Council (562183), Swedish Council for Working life and Social Research, Gemeinn{\"u}tzige 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{\textquoteright}s Hospital PhenoGenetic Project, the Swedish CAD project, the Norwegian Bone Marrow Donor Registry, the Children{\textquoteright}s Hospital of Philadelphia (CHOP), the Swedish Breast Cancer study, BRC-REFGENSEP (Piti{\'e}-Salp{\^e}tri{\`e}re Centre d{\textquoteright}Investigation Clinique (CIC) and G{\'e}n{\'e}thon) and HYPERGENES (HEALTH-F4-2007-201550). Projects received support from the German Ministry of Education and Research, the Helmholtz Zentrum M{\"u}nchen— 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{\textquoteright}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,",

year = "2011",

month = aug,

day = "11",

doi = "10.1038/nature10251",

language = "English",

volume = "476",

pages = "214--219",

journal = "Nature",

issn = "0028-0836",

number = "7359",

}

Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, 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, Boneschi, FM, 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, BAC, Cross, AH, Cusi, D, Daly, MJ, Davis, E, De Bakker, PIW, 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, SFA, 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, Leppä, 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, Rückert, 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, PMA, Smestad, C, Sørensen, PS, Søndergaard, HB, Stankovich, J, Strange, RC, Sulonen, AM, Sundqvist, E, Syvänen, 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, CNA, Wichmann, E, 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 2011, 'Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis', Nature, vol. 476, no. 7359, pp. 214-219. https://doi.org/10.1038/nature10251

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 - http://www.scopus.com/inward/record.url?scp=80051684615&partnerID=8YFLogxK

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 -

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

Abstract

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