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; Åslaug 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; 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; Wellcome Trust Case Control Consor; Peter Donnelly; Alastair Compston

doi:10.1038/nature10251

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

Journal article

Peer reviewed

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, …

Nature (London), Vol.476(7359), pp.214-219

11/08/2011

DOI: https://doi.org/10.1038/nature10251

PMCID: PMC3182531

PMID: 21833088

Abstract

genetics

GWAS

multiple sclerosis

Multiple sclerosis (OMIM 126200) 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 play 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 9772 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 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 over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

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Title: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Creators - without role: Stephen Sawcer - Heinrich Heine University Düsseldorf
Garrett Hellenthal - Heinrich Heine University Düsseldorf
Matti Pirinen - Heinrich Heine University Düsseldorf
Chris C.A. Spencer - Heinrich Heine University Düsseldorf
Nikolaos A. Patsopoulos - Heinrich Heine University Düsseldorf
Loukas Moutsianas - Heinrich Heine University Düsseldorf
Alexander Dilthey - Heinrich Heine University Düsseldorf
Zhan Su - Heinrich Heine University Düsseldorf
Colin Freeman - Heinrich Heine University Düsseldorf
Sarah E. Hunt - Heinrich Heine University Düsseldorf
Sarah Edkins - Heinrich Heine University Düsseldorf
Emma Gray - Heinrich Heine University Düsseldorf
David R. Booth - Heinrich Heine University Düsseldorf
Simon C. Potter - Heinrich Heine University Düsseldorf
An Goris - Heinrich Heine University Düsseldorf
Gavin Band - Heinrich Heine University Düsseldorf
Annette Bang Oturai - Heinrich Heine University Düsseldorf
Amy Strange - Heinrich Heine University Düsseldorf
Janna Saarela - Heinrich Heine University Düsseldorf
Céline Bellenguez - Heinrich Heine University Düsseldorf
Bertrand Fontaine - Heinrich Heine University Düsseldorf
Matthew Gillman - Heinrich Heine University Düsseldorf
Bernhard Hemmer - Heinrich Heine University Düsseldorf
Rhian Gwilliam - Heinrich Heine University Düsseldorf
Frauke Zipp - Heinrich Heine University Düsseldorf
Alagurevathi Jayakumar - Heinrich Heine University Düsseldorf
Roland Martin - Heinrich Heine University Düsseldorf
Stephen Leslie - Heinrich Heine University Düsseldorf
Stanley Hawkins - Heinrich Heine University Düsseldorf
Eleni Giannoulatou - Heinrich Heine University Düsseldorf
Sandra D’alfonso - Heinrich Heine University Düsseldorf
Hannah Blackburn - Heinrich Heine University Düsseldorf
Filippo Martinelli Boneschi - Heinrich Heine University Düsseldorf
Jennifer Liddle - Heinrich Heine University Düsseldorf
Hanne F. Harbo - Heinrich Heine University Düsseldorf
Marc L. Perez - Heinrich Heine University Düsseldorf
Anne Spurkland - Heinrich Heine University Düsseldorf
Matthew J Waller - Heinrich Heine University Düsseldorf
Marcin P. Mycko - Heinrich Heine University Düsseldorf
Michelle Ricketts - Heinrich Heine University Düsseldorf
Manuel Comabella - Heinrich Heine University Düsseldorf
Naomi Hammond - Heinrich Heine University Düsseldorf
Ingrid Kockum - Heinrich Heine University Düsseldorf
Owen T. McCann - Heinrich Heine University Düsseldorf
Maria Ban - Heinrich Heine University Düsseldorf
Pamela Whittaker - Heinrich Heine University Düsseldorf
Anu Kemppinen - Heinrich Heine University Düsseldorf
Paul Weston - Heinrich Heine University Düsseldorf
Clive Hawkins - Heinrich Heine University Düsseldorf
Sara Widaa - Heinrich Heine University Düsseldorf
John Zajicek - Heinrich Heine University Düsseldorf
Serge Dronov - Heinrich Heine University Düsseldorf
Neil Robertson - Heinrich Heine University Düsseldorf
Suzannah J. Bumpstead - Heinrich Heine University Düsseldorf
Lisa F. Barcellos - Heinrich Heine University Düsseldorf
Rathi Ravindrarajah - Heinrich Heine University Düsseldorf
Roby Abraham - Heinrich Heine University Düsseldorf
Lars Alfredsson - Heinrich Heine University Düsseldorf
Kristin Ardlie - Heinrich Heine University Düsseldorf
Cristin Aubin - Heinrich Heine University Düsseldorf
Amie Baker - Heinrich Heine University Düsseldorf
Katharine Baker - Heinrich Heine University Düsseldorf
Sergio E. Baranzini - Heinrich Heine University Düsseldorf
Laura Bergamaschi - Heinrich Heine University Düsseldorf
Roberto Bergamaschi - Heinrich Heine University Düsseldorf
Allan Bernstein - Heinrich Heine University Düsseldorf
Achim Berthele - Heinrich Heine University Düsseldorf
Mike Boggild - Heinrich Heine University Düsseldorf
Jonathan P. Bradfield - Heinrich Heine University Düsseldorf
David Brassat - Heinrich Heine University Düsseldorf
Simon A. Broadley - Heinrich Heine University Düsseldorf
Dorothea Buck - Heinrich Heine University Düsseldorf
Helmut Butzkueven - Heinrich Heine University Düsseldorf
Ruggero Capra - Heinrich Heine University Düsseldorf
William M. Carroll - Heinrich Heine University Düsseldorf
Paola Cavalla - Heinrich Heine University Düsseldorf
Elisabeth G. Celius - Heinrich Heine University Düsseldorf
Sabine Cepok - Heinrich Heine University Düsseldorf
Rosetta Chiavacci - Heinrich Heine University Düsseldorf
Françoise Clerget-Darpoux - Heinrich Heine University Düsseldorf
Katleen Clysters - Heinrich Heine University Düsseldorf
Giancarlo Comi - Heinrich Heine University Düsseldorf
Mark Cossburn - Heinrich Heine University Düsseldorf
Isabelle Cournu-Rebeix - Heinrich Heine University Düsseldorf
Mathew B. Cox - Heinrich Heine University Düsseldorf
Wendy Cozen - Heinrich Heine University Düsseldorf
Bruce A.C. Cree - Heinrich Heine University Düsseldorf
Anne H. Cross - Heinrich Heine University Düsseldorf
Daniele Cusi - Heinrich Heine University Düsseldorf
Mark J. Daly - Heinrich Heine University Düsseldorf
Emma Davis - Heinrich Heine University Düsseldorf
Paul I.W. de Bakker - Heinrich Heine University Düsseldorf
Marc Debouverie - Heinrich Heine University Düsseldorf
Marie Beatrice D’hooghe - Heinrich Heine University Düsseldorf
Katherine Dixon - Heinrich Heine University Düsseldorf
Rita Dobosi - Heinrich Heine University Düsseldorf
Bénédicte Dubois - Heinrich Heine University Düsseldorf
David Ellinghaus - Heinrich Heine University Düsseldorf
Irina Elovaara - Heinrich Heine University Düsseldorf
Federica Esposito - Heinrich Heine University Düsseldorf
Claire Fontenille - Heinrich Heine University Düsseldorf
Simon Foote - Heinrich Heine University Düsseldorf
Andre Franke - Heinrich Heine University Düsseldorf
Daniela Galimberti - Heinrich Heine University Düsseldorf
Angelo Ghezzi - Heinrich Heine University Düsseldorf
Joseph Glessner - Heinrich Heine University Düsseldorf
Refujia Gomez - Heinrich Heine University Düsseldorf
Olivier Gout - Heinrich Heine University Düsseldorf
Colin Graham - Heinrich Heine University Düsseldorf
Struan F.A. Grant - Heinrich Heine University Düsseldorf
Franca Rosa Guerini - Heinrich Heine University Düsseldorf
Hakon Hakonarson - Heinrich Heine University Düsseldorf
Per Hall - Heinrich Heine University Düsseldorf
Anders Hamsten - Heinrich Heine University Düsseldorf
Hans-Peter Hartung - Heinrich Heine University Düsseldorf
Rob N. Heard - Heinrich Heine University Düsseldorf
Simon Heath - Heinrich Heine University Düsseldorf
Jeremy Hobart - Heinrich Heine University Düsseldorf
Muna Hoshi - Heinrich Heine University Düsseldorf
Carmen Infante-Duarte - Heinrich Heine University Düsseldorf
Gillian Ingram - Heinrich Heine University Düsseldorf
Wendy Ingram - Heinrich Heine University Düsseldorf
Talat Islam - Heinrich Heine University Düsseldorf
Maja Jagodic - Heinrich Heine University Düsseldorf
Michael Kabesch - Heinrich Heine University Düsseldorf
Allan G. Kermode - Heinrich Heine University Düsseldorf
Trevor J. Kilpatrick - Heinrich Heine University Düsseldorf
Cecilia Kim - Heinrich Heine University Düsseldorf
Norman Klopp - Heinrich Heine University Düsseldorf
Keijo Koivisto - Heinrich Heine University Düsseldorf
Malin Larsson - Heinrich Heine University Düsseldorf
Mark Lathrop - Heinrich Heine University Düsseldorf
Jeannette S. Lechner-Scott - Heinrich Heine University Düsseldorf
Maurizio A. Leone - Heinrich Heine University Düsseldorf
Virpi Leppä - Heinrich Heine University Düsseldorf
Ulrika Liljedahl - Heinrich Heine University Düsseldorf
Izaura Lima Bomfim - Heinrich Heine University Düsseldorf
Robin R. Lincoln - Heinrich Heine University Düsseldorf
Jenny Link - Heinrich Heine University Düsseldorf
Jianjun Liu - Heinrich Heine University Düsseldorf
Åslaug R. Lorentzen - Heinrich Heine University Düsseldorf
Sara Lupoli - Heinrich Heine University Düsseldorf
Fabio Macciardi - Heinrich Heine University Düsseldorf
Thomas Mack - Heinrich Heine University Düsseldorf
Mark Marriott - Heinrich Heine University Düsseldorf
Vittorio Martinelli - Heinrich Heine University Düsseldorf
Deborah Mason - Heinrich Heine University Düsseldorf
Jacob L. McCauley - Heinrich Heine University Düsseldorf
Frank Mentch - Heinrich Heine University Düsseldorf
Inger-Lise Mero - Heinrich Heine University Düsseldorf
Tania Mihalova - Heinrich Heine University Düsseldorf
Xavier Montalban - Heinrich Heine University Düsseldorf
John Mottershead - Heinrich Heine University Düsseldorf
Kjell-Morten Myhr - Heinrich Heine University Düsseldorf
Paola Naldi - Heinrich Heine University Düsseldorf
William Ollier - Heinrich Heine University Düsseldorf
Alison Page - Heinrich Heine University Düsseldorf
Aarno Palotie - Heinrich Heine University Düsseldorf
Jean Pelletier - Heinrich Heine University Düsseldorf
Laura Piccio - Heinrich Heine University Düsseldorf
Trevor Pickersgill - Heinrich Heine University Düsseldorf
Fredrik Piehl - Heinrich Heine University Düsseldorf
Susan Pobywajlo - Heinrich Heine University Düsseldorf
Hong L. Quach - Heinrich Heine University Düsseldorf
Patricia P. Ramsay - Heinrich Heine University Düsseldorf
Mauri Reunanen - Heinrich Heine University Düsseldorf
Richard Reynolds - Heinrich Heine University Düsseldorf
John D. Rioux - Heinrich Heine University Düsseldorf
Mariaemma Rodegher - Heinrich Heine University Düsseldorf
Sabine Roesner - Heinrich Heine University Düsseldorf
Justin P. Rubio - Heinrich Heine University Düsseldorf
Ina-Maria Rückert - Heinrich Heine University Düsseldorf
Marco Salvetti - Heinrich Heine University Düsseldorf
Erika Salvi - Heinrich Heine University Düsseldorf
Adam Santaniello - Heinrich Heine University Düsseldorf
Catherine A. Schaefer - Heinrich Heine University Düsseldorf
Stefan Schreiber - Heinrich Heine University Düsseldorf
Christian Schulze - Heinrich Heine University Düsseldorf
Rodney J. Scott - Heinrich Heine University Düsseldorf
Finn Sellebjerg - Heinrich Heine University Düsseldorf
Krzysztof W. Selmaj - Heinrich Heine University Düsseldorf
David Sexton - Heinrich Heine University Düsseldorf
Ling Shen - Heinrich Heine University Düsseldorf
Brigid Simms-Acuna - Heinrich Heine University Düsseldorf
Sheila Skidmore - Heinrich Heine University Düsseldorf
Patrick M.A. Sleiman - Heinrich Heine University Düsseldorf
Cathrine Smestad - Heinrich Heine University Düsseldorf
Per Soelberg Sørensen - Heinrich Heine University Düsseldorf
Helle Bach Søndergaard - Heinrich Heine University Düsseldorf
Jim Stankovich - Heinrich Heine University Düsseldorf
Richard C. Strange - Heinrich Heine University Düsseldorf
Anna-Maija Sulonen - Heinrich Heine University Düsseldorf
Emilie Sundqvist - Heinrich Heine University Düsseldorf
Ann-Christine Syvänen - Heinrich Heine University Düsseldorf
Francesca Taddeo - Heinrich Heine University Düsseldorf
Bruce Taylor - Heinrich Heine University Düsseldorf
Jenefer M. Blackwell - Heinrich Heine University Düsseldorf
Pentti Tienari - Heinrich Heine University Düsseldorf
Elvira Bramon - Heinrich Heine University Düsseldorf
Ayman Tourbah - Heinrich Heine University Düsseldorf
Matthew A. Brown - Heinrich Heine University Düsseldorf
Ewa Tronczynska - Heinrich Heine University Düsseldorf
Juan P. Casas - Heinrich Heine University Düsseldorf
Niall Tubridy - Heinrich Heine University Düsseldorf
Aiden Corvin - Heinrich Heine University Düsseldorf
Jane Vickery - Heinrich Heine University Düsseldorf
Janusz Jankowski - Heinrich Heine University Düsseldorf
Pablo Villoslada - Heinrich Heine University Düsseldorf
Hugh S. Markus - Heinrich Heine University Düsseldorf
Kai Wang - Heinrich Heine University Düsseldorf
Christopher G. Mathew - Heinrich Heine University Düsseldorf
James Wason - Heinrich Heine University Düsseldorf
Colin N.A. Palmer - Heinrich Heine University Düsseldorf
H-Erich Wichmann - Heinrich Heine University Düsseldorf
Robert Plomin - Heinrich Heine University Düsseldorf
Ernest Willoughby - Heinrich Heine University Düsseldorf
Anna Rautanen - Heinrich Heine University Düsseldorf
Juliane Winkelmann - Heinrich Heine University Düsseldorf
Michael Wittig - Heinrich Heine University Düsseldorf
Richard C. Trembath - Heinrich Heine University Düsseldorf
Jacqueline Yaouanq - Heinrich Heine University Düsseldorf
Ananth C. Viswanathan - Heinrich Heine University Düsseldorf
Haitao Zhang - Heinrich Heine University Düsseldorf
Nicholas W. Wood - Heinrich Heine University Düsseldorf
Rebecca Zuvich - Heinrich Heine University Düsseldorf
Panos Deloukas - Heinrich Heine University Düsseldorf
Cordelia Langford - Heinrich Heine University Düsseldorf
Audrey Duncanson - Heinrich Heine University Düsseldorf
Jorge R. Oksenberg - Heinrich Heine University Düsseldorf
Margaret A. Pericak-Vance - Heinrich Heine University Düsseldorf
Jonathan L. Haines - Heinrich Heine University Düsseldorf
Tomas Olsson - Heinrich Heine University Düsseldorf
Jan Hillert - Heinrich Heine University Düsseldorf
Adrian J. Ivinson - Heinrich Heine University Düsseldorf
Philip L. De Jager - Heinrich Heine University Düsseldorf
Leena Peltonen - Heinrich Heine University Düsseldorf
Graeme J. Stewart - Heinrich Heine University Düsseldorf
David A. Hafler - Heinrich Heine University Düsseldorf
Stephen L. Hauser - Heinrich Heine University Düsseldorf
Gil McVean - Heinrich Heine University Düsseldorf
Wellcome Trust Case Control Consor
Peter Donnelly - Heinrich Heine University Düsseldorf
Alastair Compston - Heinrich Heine University Düsseldorf
Publication Details: Nature (London), Vol.476(7359), pp.214-219
Grant note: 085475 || WT / Wellcome Trust : 084702 || WT / Wellcome Trust : 898 || MSS_ / Multiple Sclerosis Society :
Identifiers: 9937307008331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article