Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
Wouter van RheenenAleksey ShatunovAnnelot M DekkerRussell L McLaughlinFrank P DiekstraSara L PulitRick A A van der SpekUrmo VõsaSimone de JongMatthew R RobinsonJian YangIsabella FoghPerry Tc van DoormaalGijs H P TazelaarMax KoppersAnna M BlokhuisWilliam SprovieroAshley R JonesKevin P KennaKristel R van EijkOliver HarschnitzRaymond D SchellevisWilliam J BrandsJelena MedicAndroniki MenelaouAlice VajdaNicola TicozziKuang LinBoris RogeljKatarina VrabecMetka Ravnik-GlavačBlaz KoritnikJanez ZidarLea LeonardisLeja Dolenc GrošeljStéphanie MillecampsFrançois SalachasVincent MeiningerMamede de CarvalhoSusana PintoJesus S MoraRicardo Rojas-GarcíaMeraida PolakSiddharthan ChandranShuna ColvilleRobert SwinglerKaren E MorrisonPamela J ShawJohn HardyRichard W OrrellAlan PittmanKatie SidlePietro FrattaAndrea MalaspinaSimon D ToppSusanne PetriSusanne AbdullaCarsten DrepperMichael SendtnerThomas MeyerRoel A OphoffKim A StaatsMartina Wiedau-PazosCatherine Lomen-HoerthVivanna M Van DeerlinJohn Q TrojanowskiLauren ElmanLeo McCluskeyA Nazli BasakCeren TuncaHamid HamzeiyYesim ParmanThomas MeitingerPeter LichtnerMilena Radivojkov-BlagojevicChristian R AndresCindy MaurelGilbert BensimonBernhard LandwehrmeyerAlexis BriceChristine A M PayanSafaa Saker-DelyeAlexandra DürrNicholas W WoodLukas TittmannWolfgang LiebAndre FrankeMarcella RietschelSven CichonMarkus M NöthenPhillippe AmouyelChristophe TzourioJean-François DartiguesAndre G UitterlindenFernando RivadeneiraKarol EstradaAlbert HofmanCharles CurtisHylke M BlauwAnneke J van der KooiMarianne de VisserAn GorisMarkus WeberChristopher E ShawBradley N SmithOrietta PansarasaCristina CeredaRoberto Del BoGiacomo P ComiSandra D'AlfonsoCinzia BertolinGianni SorarùLetizia MazziniViviana PensatoCinzia GelleraCinzia TilocaAntonia RattiAndrea CalvoCristina MogliaMaura BrunettiSimona ArcutiRosa CapozzoChiara ZeccaChristian LunettaSilvana PencoNilo RivaAlessandro PadovaniMassimiliano FilostoBernard MullerRobbert Jan Stuitnull nullnull nullnull nullnull nullnull nullnull nullIan BlairKatharine ZhangEmily P McCannJennifer A FifitaGarth A NicholsonDominic B RoweRoger PamphlettMatthew C KiernanJulian GrosskreutzOtto W WitteThomas RingerTino PrellBeatrice StubendorffIngo KurthChristian A HübnerP Nigel LeighFederico CasaleAdriano ChioEttore BeghiElisabetta PupilloRosanna TortelliGiancarlo LogroscinoJohn PowellAlbert C LudolphJochen H WeishauptWim RobberechtPhilip Van DammeLude H FrankeTune H PersRobert H BrownJonathan D GlassJohn E LandersOrla HardimanPeter M AndersenPhilippe CorciaPatrick Vourc'hVincenzo SilaniNaomi R WrayPeter M VisscherPaul I W de BakkerMichael A van EsRonald Jeroen PasterkampCathryn M LewisGerome BreenAmmar Al-ChalabiLeonard H van den BergJan H VeldinkPublished in: Nature genetics (2016)
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.