6533b838fe1ef96bd12a487b
RESEARCH PRODUCT
Low frequency and rare coding variation contributes to multiple sclerosis risk
Fredrik KarpeGraeme StewartJan HillertElisabetta MasciaMatt J. NevilleVerena GrummelJonathan L. HainesKate FitzgeraldBernhard HemmerJulia Y MescheriakovaBenedicte A. LieEfthimios LuessiFederica EspositoAndreas ZieglerIoanna KonidariCristin MccabeKeith R. EdwardsRoland MartinDaniele CusiElisabeth Gulowsen CeliusCristina AgliardiAnne SpurklandGeorgios M. HadjigeorgiouLena Guillot-noelAntonios BayasUwe K. ZettlKjell-morten MyhrMaria BanRogier Q. HintzenFrauke ZippMireia SospedraTill F. M. AndlauerAdrian J. IvinsonMary F. DavisMark LathropDaniela GalimbertiPierre-antoine GourraudGenevieve LachanceBruce A.c. CreeRobin LemmensAshley BeechamSteffan D. BosBruce V. TaylorMaurizio LeoneManuel ComabellaMaja JagodicHelle Bach SøndergaardDavid A. HaflerIngrid KockumNadia BarizzoneRalf GoldTania KümpfelPer Soelberg SørensenSeema KalraAn GorisPhilip Van DammeMarie B. D'hoogheCathy SchaeferEfthimios DardiotisAlastair CompstonLotti TajooriSandra D'alfonsoIlijas JelcicStephen SawcerBrigitte WildemannFriedemann PaulLise Wegner ThoernerSilvia DelgadoTomas OlssonMitja MitrovicHayrettin TumaniHenrik UllumLisa F. BarcellosXavier MontalbanEllen LathiFinn SellebjergThomas WergeChristina M. LillPernilla StridhPaul I.w. De BakkerCornelia M. Van DuijnJyoti KhadakeJac CharlesworthMelissa SorosinaChristiane GasperiStephen L. HauserAnne H. CrossIsabelle Cournu-rebeixNikolaos A. PatsopoulosFredrik PiehlLars AlfredssonBertrand FontaineMarieme DembeleMargaret A. Pericak-vanceJanna SaarelaUlf ZiemannAnnette Bang OturaiStacy J. CaillierJorge R. OksenbergBénédicte DuboisBjörn TackenbergChristoph HeesenJacob L. MccauleyFlorian Then BerghClemens WarnkeSergio E. BaranziniPeter A. CalabresiChris CotsapasClive HawkinsMartin StangelHakon HakonarsonSandra VukusikChristiane GraetzHeinz WiendlHoward L. WeinerLaura PiccioGiancarlo ComiRalf A. LinkerLuisa BernardinelliCristoforo ComiFilippo Martinelli-boneschiHanne F. HarboDorothea BuckClara P. ManriqueDavid R. BoothBenjamin KnierPhilip L. De JagerViola PongratzLaura FerrèVincent DamotteAdam SantanielloTheresa DankowskiPirro G. Hysisubject
Genetics0303 health sciencesLinkage disequilibriumMultiple sclerosisDiseaseBiologyHeritabilitymedicine.disease3. Good health03 medical and health sciences0302 clinical medicinemedicineEpistasisCoding regionGene030217 neurology & neurosurgery030304 developmental biologyGenetic associationdescription
AbstractMultiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-03-23 |