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

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

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Authors

  • 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
  • Celine Bellenguez
  • And 223 others
  • 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
  • Francoise 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
  • Benedicte 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 Leppa
  • 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
  • Johnd. Rioux
  • Mariaemma Rodegher
  • Sabine Roesner
  • Justin P. Rubio
  • Ina-Maria Rueckert
  • 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 Sorensen
  • Helle Bach Sondergaard
  • Jim Stankovich
  • Richard C. Strange
  • Anna-Maija Sulonen
  • Emilie Sundqvist
  • Ann-Christine Syvaenen
  • 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
  • H-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
  • Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co

Research units

    Info

    Original languageEnglish
    Pages214-219
    Number of pages6
    JournalNature
    Journal publication date11 Aug 2011
    Volume476
    Issue7359
    DOIs
    StatePublished

    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(1). 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(2,3), 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(4). Modestly powered genome-wide association studies (GWAS)(5-10) 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(11). 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.

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