Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. / Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C. A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Celine; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'alfonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J.; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Francoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A. C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I. W.; Debouverie, Marc; D'hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Benedicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F. A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppa, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, Johnd.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rueckert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M. A.; Smestad, Cathrine; Sorensen, Per Soelberg; Sondergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvaenen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N. A.; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair; Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co.
In: Nature, Vol. 476, No. 7359, 11.08.2011, p. 214-219.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
A1 - Sawcer,Stephen
A1 - Hellenthal,Garrett
A1 - Pirinen,Matti
A1 - Spencer,Chris C. A.
A1 - Patsopoulos,Nikolaos A.
A1 - Moutsianas,Loukas
A1 - Dilthey,Alexander
A1 - Su,Zhan
A1 - Freeman,Colin
A1 - Hunt,Sarah E.
A1 - Edkins,Sarah
A1 - Gray,Emma
A1 - Booth,David R.
A1 - Potter,Simon C.
A1 - Goris,An
A1 - Band,Gavin
A1 - Oturai,Annette Bang
A1 - Strange,Amy
A1 - Saarela,Janna
A1 - Bellenguez,Celine
A1 - Fontaine,Bertrand
A1 - Gillman,Matthew
A1 - Hemmer,Bernhard
A1 - Gwilliam,Rhian
A1 - Zipp,Frauke
A1 - Jayakumar,Alagurevathi
A1 - Martin,Roland
A1 - Leslie,Stephen
A1 - Hawkins,Stanley
A1 - Giannoulatou,Eleni
A1 - D'alfonso,Sandra
A1 - Blackburn,Hannah
A1 - Boneschi,Filippo Martinelli
A1 - Liddle,Jennifer
A1 - Harbo,Hanne F.
A1 - Perez,Marc L.
A1 - Spurkland,Anne
A1 - Waller,Matthew J.
A1 - Mycko,Marcin P.
A1 - Ricketts,Michelle
A1 - Comabella,Manuel
A1 - Hammond,Naomi
A1 - Kockum,Ingrid
A1 - McCann,Owen T.
A1 - Ban,Maria
A1 - Whittaker,Pamela
A1 - Kemppinen,Anu
A1 - Weston,Paul
A1 - Hawkins,Clive
A1 - Widaa,Sara
A1 - Zajicek,John
A1 - Dronov,Serge
A1 - Robertson,Neil
A1 - Bumpstead,Suzannah J.
A1 - Barcellos,Lisa F.
A1 - Ravindrarajah,Rathi
A1 - Abraham,Roby
A1 - Alfredsson,Lars
A1 - Ardlie,Kristin
A1 - Aubin,Cristin
A1 - Baker,Amie
A1 - Baker,Katharine
A1 - Baranzini,Sergio E.
A1 - Bergamaschi,Laura
A1 - Bergamaschi,Roberto
A1 - Bernstein,Allan
A1 - Berthele,Achim
A1 - Boggild,Mike
A1 - Bradfield,Jonathan P.
A1 - Brassat,David
A1 - Broadley,Simon A.
A1 - Buck,Dorothea
A1 - Butzkueven,Helmut
A1 - Capra,Ruggero
A1 - Carroll,William M.
A1 - Cavalla,Paola
A1 - Celius,Elisabeth G.
A1 - Cepok,Sabine
A1 - Chiavacci,Rosetta
A1 - Clerget-Darpoux,Francoise
A1 - Clysters,Katleen
A1 - Comi,Giancarlo
A1 - Cossburn,Mark
A1 - Cournu-Rebeix,Isabelle
A1 - Cox,Mathew B.
A1 - Cozen,Wendy
A1 - Cree,Bruce A. C.
A1 - Cross,Anne H.
A1 - Cusi,Daniele
A1 - Daly,Mark J.
A1 - Davis,Emma
A1 - de Bakker,Paul I. W.
A1 - Debouverie,Marc
A1 - D'hooghe,Marie Beatrice
A1 - Dixon,Katherine
A1 - Dobosi,Rita
A1 - Dubois,Benedicte
A1 - Ellinghaus,David
A1 - Elovaara,Irina
A1 - Esposito,Federica
A1 - Fontenille,Claire
A1 - Foote,Simon
A1 - Franke,Andre
A1 - Galimberti,Daniela
A1 - Ghezzi,Angelo
A1 - Glessner,Joseph
A1 - Gomez,Refujia
A1 - Gout,Olivier
A1 - Graham,Colin
A1 - Grant,Struan F. A.
A1 - Guerini,Franca Rosa
A1 - Hakonarson,Hakon
A1 - Hall,Per
A1 - Hamsten,Anders
A1 - Hartung,Hans-Peter
A1 - Heard,Rob N.
A1 - Heath,Simon
A1 - Hobart,Jeremy
A1 - Hoshi,Muna
A1 - Infante-Duarte,Carmen
A1 - Ingram,Gillian
A1 - Ingram,Wendy
A1 - Islam,Talat
A1 - Jagodic,Maja
A1 - Kabesch,Michael
A1 - Kermode,Allan G.
A1 - Kilpatrick,Trevor J.
A1 - Kim,Cecilia
A1 - Klopp,Norman
A1 - Koivisto,Keijo
A1 - Larsson,Malin
A1 - Lathrop,Mark
A1 - Lechner-Scott,Jeannette S.
A1 - Leone,Maurizio A.
A1 - Leppa,Virpi
A1 - Liljedahl,Ulrika
A1 - Bomfim,Izaura Lima
A1 - Lincoln,Robin R.
A1 - Link,Jenny
A1 - Liu,Jianjun
A1 - Lorentzen,Aslaug R.
A1 - Lupoli,Sara
A1 - Macciardi,Fabio
A1 - Mack,Thomas
A1 - Marriott,Mark
A1 - Martinelli,Vittorio
A1 - Mason,Deborah
A1 - McCauley,Jacob L.
A1 - Mentch,Frank
A1 - Mero,Inger-Lise
A1 - Mihalova,Tania
A1 - Montalban,Xavier
A1 - Mottershead,John
A1 - Myhr,Kjell-Morten
A1 - Naldi,Paola
A1 - Ollier,William
A1 - Page,Alison
A1 - Palotie,Aarno
A1 - Pelletier,Jean
A1 - Piccio,Laura
A1 - Pickersgill,Trevor
A1 - Piehl,Fredrik
A1 - Pobywajlo,Susan
A1 - Quach,Hong L.
A1 - Ramsay,Patricia P.
A1 - Reunanen,Mauri
A1 - Reynolds,Richard
A1 - Rioux,Johnd.
A1 - Rodegher,Mariaemma
A1 - Roesner,Sabine
A1 - Rubio,Justin P.
A1 - Rueckert,Ina-Maria
A1 - Salvetti,Marco
A1 - Salvi,Erika
A1 - Santaniello,Adam
A1 - Schaefer,Catherine A.
A1 - Schreiber,Stefan
A1 - Schulze,Christian
A1 - Scott,Rodney J.
A1 - Sellebjerg,Finn
A1 - Selmaj,Krzysztof W.
A1 - Sexton,David
A1 - Shen,Ling
A1 - Simms-Acuna,Brigid
A1 - Skidmore,Sheila
A1 - Sleiman,Patrick M. A.
A1 - Smestad,Cathrine
A1 - Sorensen,Per Soelberg
A1 - Sondergaard,Helle Bach
A1 - Stankovich,Jim
A1 - Strange,Richard C.
A1 - Sulonen,Anna-Maija
A1 - Sundqvist,Emilie
A1 - Syvaenen,Ann-Christine
A1 - Taddeo,Francesca
A1 - Taylor,Bruce
A1 - Blackwell,Jenefer M.
A1 - Tienari,Pentti
A1 - Bramon,Elvira
A1 - Tourbah,Ayman
A1 - Brown,Matthew A.
A1 - Tronczynska,Ewa
A1 - Casas,Juan P.
A1 - Tubridy,Niall
A1 - Corvin,Aiden
A1 - Vickery,Jane
A1 - Jankowski,Janusz
A1 - Villoslada,Pablo
A1 - Markus,Hugh S.
A1 - Wang,Kai
A1 - Mathew,Christopher G.
A1 - Wason,James
A1 - Palmer,Colin N. A.
A1 - Wichmann,H-Erich
A1 - Plomin,Robert
A1 - Willoughby,Ernest
A1 - Rautanen,Anna
A1 - Winkelmann,Juliane
A1 - Wittig,Michael
A1 - Trembath,Richard C.
A1 - Yaouanq,Jacqueline
A1 - Viswanathan,Ananth C.
A1 - Zhang,Haitao
A1 - Wood,Nicholas W.
A1 - Zuvich,Rebecca
A1 - Deloukas,Panos
A1 - Langford,Cordelia
A1 - Duncanson,Audrey
A1 - Oksenberg,Jorge R.
A1 - Pericak-Vance,Margaret A.
A1 - Haines,Jonathan L.
A1 - Olsson,Tomas
A1 - Hillert,Jan
A1 - Ivinson,Adrian J.
A1 - De Jager,Philip L.
A1 - Peltonen,Leena
A1 - Stewart,Graeme J.
A1 - Hafler,David A.
A1 - Hauser,Stephen L.
A1 - McVean,Gil
A1 - Donnelly,Peter
A1 - Compston,Alastair
A1 - Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co
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,Celine
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,Francoise
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,Benedicte
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 - Leppa,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,Johnd.
AU - Rodegher,Mariaemma
AU - Roesner,Sabine
AU - Rubio,Justin P.
AU - Rueckert,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 - Sorensen,Per Soelberg
AU - Sondergaard,Helle Bach
AU - Stankovich,Jim
AU - Strange,Richard C.
AU - Sulonen,Anna-Maija
AU - Sundqvist,Emilie
AU - Syvaenen,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,H-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
AU - Wellcome Trust Case Control Consor, Int Multiple Sclerosis Genetics Co
PY - 2011/8/11
Y1 - 2011/8/11
N2 - <p>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.</p>
AB - <p>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.</p>
KW - GENOME-WIDE ASSOCIATION
KW - SUSCEPTIBILITY LOCI
KW - HETEROGENEITY
KW - HAPLOTYPES
KW - VARIANTS
KW - ALLELES
U2 - 10.1038/nature10251
DO - 10.1038/nature10251
M1 - Article
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7359
VL - 476
SP - 214
EP - 219
ER -