6533b825fe1ef96bd128321c

RESEARCH PRODUCT

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

Per HallSimon C. PotterRichard ReynoldsRobert HeardGil McveanAn GorisJoseph T. GlessnerPamela WhittakerNiall TubridyOlivier GoutAnn-christine SyvaenenLeena PeltonenBénédicte DuboisAnders HamstenAlastair CompstonHugh S. MarkusMariaemma RodegherLisa F. BarcellosLisa F. BarcellosWendy CozenRosetta M. ChiavacciJenefer M. BlackwellJenefer M. BlackwellJenefer M. BlackwellWilliam M. CarrollPatricia P. RamsayAmie BakerKrzysztof SelmajSerge DronovZhan SuC. SmestadStanley HawkinsJanna SaarelaMatti PirinenSabine CepokGavin BandNorman KloppSimon HeathSandra D'alfonsoPeter DonnellyPeter DonnellyIna-maria RueckertDeborah F. MasonAlagurevathi JayakumarHakon HakonarsonHakon HakonarsonCecilia KimColin FreemanJeannette Lechner-scottMarc DebouverieNeil RobertsonInger-lise MeroPaola CavallaSabine RoesnerH-erich WichmannH-erich WichmannDaniele CusiWendy IngramWendy IngramSarah EdkinsTania MihalovaMark J. DalyMark J. DalyMark MarriottRoland MartinAdrian J. IvinsonHong L. QuachJeremy HobartJeremy HobartFilippo Martinelli-boneschiCarmen Infante-duarteCatherine SchaeferIrina ElovaaraJonathan L. HainesJohn ZajicekJohn ZajicekMichelle RickettsAnanth C. ViswanathanAnanth C. ViswanathanColin A. GrahamAllan G. KermodeHelmut ButzkuevenKai WangJohn MottersheadFrancesca TaddeoStefan SchreiberAarno PalotieTrevor PickersgillNaomi HammondDavid A. HaflerDavid A. HaflerRobert PlominRobin R. LincolnDavid SextonJianjun LiuFinn SellebjergFrançoise Clerget-darpouxDavid BrassatSarah E. HuntPer Soelberg SørensenVittorio MartinelliEleni GiannoulatouPaul I.w. De BakkerPaul I.w. De BakkerPaul I.w. De BakkerAlexander T. DiltheyStephen LeslieUlrika LiljedahlHanne F. HarboHanne F. HarboAlison PageKeijo KoivistoIngrid KockumStephen L. HauserEwa TronczynskaAyman TourbahK BakerPanos DeloukasHannah BlackburnJanusz JankowskiMauri ReunanenTrevor J. KilpatrickSheila SkidmoreSergio E. BaranziniNicholas W. WoodFredrik PiehlLars AlfredssonDaniela GalimbertiFederica EspositoMarco SalvettiJennifer LiddleJenny LinkHelle Bach SøndergaardSuzannah BumpsteadJonathan P. BradfieldRichard C. StrangeCéline BellenguezDavid R. BoothRefujia GomezMichael WittigMatthew A. BrownLaura BergamaschiElisabeth Gulowsen CeliusWilliam E R OllierJuan P. CasasLing ShenLoukas MoutsianasFabio MacciardiFabio MacciardiAnne H. CrossMaja JagodicMarie B. D'hoogheTomas OlssonMark D. CossburnO. T. MccannJustin P. RubioIsabelle Cournu-rebeixStruan F.a. GrantStruan F.a. GrantColin N. A. PalmerMatthew W. GillmanJohn D. RiouxJohn D. RiouxChristopher G. MathewMaria BanAnna-maija SulonenGarrett HellenthalDorothea BuckJorge R. OksenbergFrauke ZippJames WasonStephen SawcerFranca Rosa GueriniClive HawkinsCristin AubinElvira BramonPaul A. WestonAndre FrankeLaura PiccioJane VickeryJane VickeryNikolaos A. PatsopoulosNikolaos A. PatsopoulosNikolaos A. PatsopoulosJacob L. MccauleyKristin G. ArdlieA. StrangeMarcin P. MyckoRichard C. TrembathGiancarlo ComiGillian IngramGraeme J. StewartAllan L. BernsteinEmilie SundqvistXavier MontalbanJuliane WinkelmannRhian GwilliamRuggero CapraBruce V. TaylorMaurizio LeoneBrigid Simms-acunaEmma J. DavisBertrand FontaineChris C. A. SpencerMalin LarssonHans-peter HartungEmma GrayVirpi LeppaPablo VillosladaAudrey DuncansonÅSlaug R. LorentzenÅSlaug R. LorentzenRathi RavindrarajahIzaura Lima BomfimChristian SchulzeTalat IslamManuel ComabellaRita DobosiSimon BroadleyBernhard HemmerMargaret A. Pericak-vanceJan HillertMichael KabeschJ. YaouanqMark LathropAngelo GhezziRodney J. ScottK DixonJean PelletierAnnette Bang OturaiMike BoggildPhilip L. De JagerPhilip L. De JagerPhilip L. De JagerAnne SpurklandM. PerezRoby AbrahamPentti J. TienariMatthew WallerKatleen ClystersAdam SantanielloDavid EllinghausCordelia LangfordAnna RautanenFrank D. MentchAchim BertheleKjell-morten MyhrSimon J. FooteThomas M. MackBruce A.c. CreeSusan PobywajloErnest WilloughbyHaitao ZhangM. B. CoxAnu KemppinenMuna HoshiSara WidaaClaire FontenilleErika SalviSara LupoliAiden CorvinRoberto BergamaschiJim StankovichRebecca L. ZuvichPaola NaldiPatrick M. A. Sleiman

subject

Immunity Cellular/geneticsCellular immunityMultiple SclerosisGenome-wide association studyCLEC16ABiologyPolymorphism Single NucleotideCell Differentiation/immunologyEurope/ethnologyMajor Histocompatibility Complex/geneticsMajor Histocompatibility Complex03 medical and health sciences0302 clinical medicinemedicineGenetic predispositionHumansGenetic Predisposition to DiseaseHLA-A Antigens/geneticsAlleles030304 developmental biologyGenetic associationGenetics0303 health sciencesImmunity CellularMultidisciplinaryHLA-A AntigensGenome HumanMultiple sclerosisGenetic Predisposition to Disease/geneticsHLA-DR Antigens/geneticsLymphocyte differentiationCell DifferentiationHLA-DR AntigensT-Lymphocytes Helper-InducerRC346medicine.diseasePolymorphism Single Nucleotide/geneticsGenetic architecture3. Good healthEuropeSample SizeImmunologyGenome Human/geneticsMultiple Sclerosis/genetics030217 neurology & neurosurgeryT-Lymphocytes Helper-Inducer/cytologyGenome-Wide Association StudyHLA-DRB1 Chains

description

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.

yearjournalcountryeditionlanguage
2011-01-01
10.1038/nature10251https://doi.org/10.1038/nature10251