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

Journal: Nature
Published:
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.

Authors
Matti Pirinen, Chris C Spencer, Nikolaos Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan Su, Colin Freeman, Sarah Hunt, Sarah Edkins, Emma Gray, David Booth, Simon Potter, An Goris, Gavin Band, Annette 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 Harbo, Marc Perez, Anne Spurkland, Matthew Waller, Marcin Mycko, Michelle Ricketts, Manuel Comabella, Naomi Hammond, Ingrid Kockum, Owen Mccann, Maria Ban, Pamela Whittaker, Anu Kemppinen, Paul Weston, Clive Hawkins, Sara Widaa, John Zajicek, Serge Dronov, Neil Robertson, Suzannah Bumpstead, Lisa Barcellos, Rathi Ravindrarajah, Roby Abraham, Lars Alfredsson, Kristin Ardlie, Cristin Aubin, Amie Baker, Katharine Baker, Sergio Baranzini, Laura Bergamaschi, Roberto Bergamaschi, Allan Bernstein, Achim Berthele, Mike Boggild, Jonathan Bradfield, David Brassat, Simon Broadley, Dorothea Buck, Helmut Butzkueven, Ruggero Capra, William Carroll, Paola Cavalla, Elisabeth Celius, Sabine Cepok, Rosetta Chiavacci, Françoise Clerget Darpoux, Katleen Clysters, Giancarlo Comi, Mark Cossburn, Isabelle Cournu Rebeix, Mathew Cox, Wendy Cozen, Bruce A Cree, Anne Cross, Daniele Cusi, Mark Daly, Emma Davis, Paul De Bakker, Marc Debouverie, Marie 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 Grant, Franca Guerini, Hakon Hakonarson, Per Hall, Anders Hamsten, Hans-peter Hartung, Rob Heard, Simon Heath, Jeremy Hobart, Muna Hoshi, Carmen Infante Duarte, Gillian Ingram, Wendy Ingram, Talat Islam, Maja Jagodic, Michael Kabesch, Allan Kermode, Trevor Kilpatrick, Cecilia Kim, Norman Klopp, Keijo Koivisto, Malin Larsson, Mark Lathrop, Jeannette Lechner Scott, Maurizio Leone, Virpi Leppä, Ulrika Liljedahl, Izaura Bomfim, Robin Lincoln, Jenny Link, Jianjun Liu, Aslaug Lorentzen, Sara Lupoli, Fabio Macciardi, Thomas Mack, Mark Marriott, Vittorio Martinelli, Deborah Mason, Jacob 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 Quach, Patricia Ramsay, Mauri Reunanen, Richard Reynolds, John Rioux, Mariaemma Rodegher, Sabine Roesner, Justin Rubio, Ina-maria Rückert, Marco Salvetti, Erika Salvi, Adam Santaniello, Catherine Schaefer, Stefan Schreiber, Christian Schulze, Rodney Scott, Finn Sellebjerg, Krzysztof Selmaj, David Sexton, Ling Shen, Brigid Simms Acuna, Sheila Skidmore, Patrick M Sleiman, Cathrine Smestad, Per Sørensen, Helle Søndergaard, Jim Stankovich, Richard Strange, Anna-maija Sulonen, Emilie Sundqvist, Ann-christine Syvänen, Francesca Taddeo, Bruce Taylor, Jenefer Blackwell, Pentti Tienari, Elvira Bramon, Ayman Tourbah, Matthew Brown, Ewa Tronczynska, Juan Casas, Niall Tubridy, Aiden Corvin, Jane Vickery, Janusz Jankowski, Pablo Villoslada, Hugh Markus, Kai Wang, Christopher Mathew, James Wason, Colin N Palmer, H-erich Wichmann, Robert Plomin, Ernest Willoughby, Anna Rautanen, Juliane Winkelmann, Michael Wittig, Richard Trembath, Jacqueline Yaouanq, Ananth Viswanathan, Haitao Zhang, Nicholas Wood, Rebecca Zuvich, Panos Deloukas, Cordelia Langford, Audrey Duncanson, Jorge Oksenberg, Margaret Pericak Vance, Jonathan Haines, Tomas Olsson, Jan Hillert, Adrian Ivinson, Philip De Jager, Leena Peltonen, Graeme Stewart, David Hafler, Stephen Hauser, Gil Mcvean, Peter Donnelly, Alastair Compston
Relevant Conditions

Multiple Sclerosis (MS)