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.

DOI: 10.1038/nature10251

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@inproceedings{Sawcer2011GeneticRA, title={Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis}, author={Stephen Sawcer and Garrett Hellenthal and Matti Pirinen and Chris C.A. Spencer and Nikolaos A. Patsopoulos and Loukas Moutsianas and Alexander Dilthey and Zhan Su and Colin Freeman and Sarah E. Hunt and Sarah Edkins and Emma Gray and David R. Booth and Simon C. Potter and An Goris and Gavin Band and Annette Bang Oturai 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 Filippo Martinelli Boneschi and Jennifer Liddle and Hanne F. Harbo and Marc L. Perez and Anne Spurkland and Matthew J Waller and Marcin P. Mycko and Michelle Ricketts and Manuel Comabella and Naomi Hammond and Ingrid Kockum and Owen T. McCann 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 Suzannah J. Bumpstead and Lisa F. Barcellos and Rathi Ravindrarajah and Roby Abraham and Lars Alfredsson and Kristin Ardlie and Cristin Aubin and Amie Baker and Katharine Baker and Sergio E. Baranzini and Laura Bergamaschi and Roberto Bergamaschi and Allan Bernstein and Achim Berthele and Mike Boggild and Jonathan P. Bradfield and David Brassat and Simon A. Broadley and Dorothea Buck and Helmut Butzkueven and Ruggero Capra and William M. Carroll and Paola Cavalla and Elisabeth G. Celius and Sabine Cepok and Rosetta Chiavacci and Françoise Clerget-Darpoux and Katleen Clysters and Giancarlo Comi and Mark Cossburn and Isabelle Cournu-Rebeix and Mathew B. Cox and Wendy Cozen and Bruce A.C. Cree and Anne H. Cross and Daniele Cusi and Mark J. Daly and Emma Davis and Paul I.W. de Bakker and Marc Debouverie and Marie Beatrice D’hooghe 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 Struan F.A. Grant and Franca Rosa Guerini and Hakon Hakonarson and Per Hall and Anders Hamsten and Hans-Peter Hartung and Rob N. Heard 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 Allan G. Kermode and Trevor J. Kilpatrick and Cecilia Kim and Norman Klopp and Keijo Koivisto and Malin Larsson and Mark Lathrop and Jeannette S. Lechner-Scott and Maurizio A. Leone and Virpi Lepp{\"a} and Ulrika Liljedahl and Izaura Lima Bomfim and Robin R. Lincoln and Jenny Link and Jianjun Liu and {\AA}slaug R. Lorentzen and Sara Lupoli and Fabio Macciardi and Thomas Mack and Mark Marriott and Vittorio Martinelli and Deborah Mason and Jacob L. McCauley and Frank Mentch and Inger-Lise Mero and Tania Mihalova and Xavier Montalban and John Mottershead and Kjell-Morten Myhr 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 Hong L. Quach and Patricia P. Ramsay and Mauri Reunanen and Richard Reynolds and John D. Rioux and Mariaemma Rodegher and Sabine Roesner and Justin P. Rubio and Ina-Maria R{\"{u}ckert and Marco Salvetti and Erika Salvi and Adam Santaniello and Catherine A. Schaefer and Stefan Schreiber and Christian Schulze and Rodney J. Scott and Finn Sellebjerg and Krzysztof W. Selmaj and David Sexton and Ling Shen and Brigid Simms-Acuna and Sheila Skidmore and Patrick M.A. Sleiman and Cathrine Smestad and Per Soelberg S\orensen and Helle Bach S\ondergaard and Jim Stankovich and Richard C. Strange and Anna-Maija Sulonen and Emilie Sundqvist and Ann-Christine Syv{\"a}nen and Francesca Taddeo and Bruce Taylor and Jenefer M. Blackwell and Pentti Tienari and Elvira Bramon and Ayman Tourbah and Matthew A. Brown and Ewa Tronczynska and Juan P. Casas and Niall Tubridy and Aiden Corvin and Jane Vickery and Janusz Jankowski and Pablo Villoslada and Hugh S. Markus and Kai Wang and Christopher G. Mathew and James Wason and Colin N.A. Palmer and H-Erich Wichmann and Robert Plomin and Ernest Willoughby and Anna Rautanen and Juliane Winkelmann and Michael Wittig and Richard C. Trembath and Jacqueline Yaouanq and Ananth C. Viswanathan and Haitao Zhang and Nicholas W. Wood and Rebecca Zuvich and Panos Deloukas and Cordelia Langford and Audrey Duncanson and Jorge R. Oksenberg and Margaret A. Pericak-Vance and Jonathan L. Haines and Tomas Olsson and Jan Hillert and Adrian J. Ivinson and Philip L. De Jager and Leena Peltonen and Graeme J. Stewart and David A. Hafler and Stephen L. Hauser and Gil McVean and Peter Donnelly and Alastair Compston}, booktitle={Nature}, year={2011} }