biostudies-literatureNicolas ABLRD VAIntramural NIH HHSNIA NIH HHSNIEHS NIH HHSNHLBI NIH HHSMotor Neurone Disease AssociationRosetreesAcademy of Medical SciencesMedical Research FoundationEuropean Research CouncilMedical Research CouncilNIMHD NIH HHSNational Institute for Health Research (NIHR)MRF_NINDS NIH HHSWellcome Trust1267-1288https://www.ebi.ac.uk/biostudies/studies/S-EPMC5867896biostudies-literatureUnknown97(6)To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survivaNeuronGenome-wide Analyses Identify KIF5A as a Novel ALS Gene.PMC5867896UKDRI-6001P30 AG013846MCLAUGHLIN/OCT15/957-799MC_PC_17115MR/L021803/1Z01 AG000949P50 AG005146R56 NS061867P01 NS084974FRATTA/JAN15/946-795SMITH/APR16/847-791MR/M008606/1M599P01 AG017586R35 NS097261MALASPINA/APR13/817-791I01 BX002466SHAW/NOV14/985-797340429SGL018\1007G0600974R01 NS073873SMITH/OCT16/888-792MRF-060-0003-RG-SMITHNF-SI-0512-10082MR/K01014X/1SHAW/APR15/933-794K23 ES027221U54 NS092091CL-2015-04-001NF-SI-0617-10077U54 NS091046MR/L501529/1G0500289K25 HL121295TURNER/OCT18/989-797R01 MD009164ZIA AG000933MR/L016397/1TURNER/JAN13/944-795ALCHALABI-DOBSON/APR14/829-791G0900688MR/R024804/1R01 NS061867Dardiotis ECorongiu DBenigni MTwine NABedlack RVan Damme PBlair IPFloeter MKVourch PRogaeva ESLAGEN ConsortiumMalaspina AMandrioli JDominov JATen Asbroek ALMAHarms MBMarrosu MGMill JMcLaughlin RCuccu SLee EBAl Kheifat ASoraru GSidle KCVan Deerlin VMValori MMiddelkoop BCasale FJenkins LCaponnetto CBowser RSmith BNvan Vugt JPetrucci AEsteban-Perez JRedondo AGLima LTaylor JPHamdalla HLandi FDrory VETazelaar GCooper-Knock JLu YFSalvi FPickering-Brown SKowall NWvan Eijk KPensato VBarohn RFogh IAndersen PCouratier PPenco SVance CCau TBvan Damme PGagliardi SRavits JMJohnson JODel Bo RCox GATremolizzo LTienari PCooper GMMarrali GJansson LOrigone PWaite LLClavelou PInghilleri MZuchner SLunetta CKolb SJFuda GAl-Sarraj SMarrosu FLudolph ACFinkbeiner SMorrison KEArcila-Londono XGlass JDCastellotti BITALSGEN ConsortiumHarris TPioro EGoutman SASapp PCDion PARothstein JDOstrow LWAbramzon YVeldink JHNeto MMvan den Berg LManera UGitler ADLauria GMaragakis NJFeldman ELCarrera PMancardi GCammarosano SBroach JEicher JDRaphael ARPioro EPFaghri FVan Eyk JEGkazi ASFasano AGwathmey KMouzat KLogroscino GMarinou KMcCauley JFifita JAHardiman OBartolomei IMacGowan DJLColombrita CGlass JMelis MLumbroso SZollino MBorghero GPenny MNalls MATiloca CBruijn LMora JSRen ZCampbell RHShaw CHan YBerry JDPiccirillo GShneider NAAndersen PMShaw PHammell MGTanel RConte ASims KBBasak ANGibbs JRWeishaupt JHShaw PJIacoangeli ATroakes CBoone BEChia RPiras VAllen ASLa Bella VNewhouse SProject MinE ALS Sequencing ConsortiumPal SDekker AWyman SKDe Marchi FSvendsen CNRampersaud EArepalli SManiatis TRobberecht WGiannini FMoglia CHussain SPinter GLALS Sequencing ConsortiumBaxi EMeitinger TMeininger VD'Alfonso SArosio ABertolin CBattistini SRollinson SDunckley TLLoi DBrady CBTrivedi JHornstein ENicholson GAPetrovski SKiernan MLevy SEFerrarese CLasseigne BNHardy JGoldstein DBHide WClayman CTroncoso JCMunoz-Blanco JLMaderna LMcLaughlin RLLuigetti MOcchineri PLacomis DPliner HASingleton ABTopp SDGrassano Mde Belleroche JLagrange EHeiman-Patterson TAbhyankar AChio ACooley AParish LDAl-Chalabi AVan Eyk JSproviero WCaredda CAsress SMusunuri RLKhan SGibson SRivera AMSimone IChesi AWilliams KLVan Es MAKwan JLogullo FOElman LZinman LCereda CBauer DCStaropoli JFMoisse MKatz JWalk DMorrison KTicca AGibson SBMoreno CAMGellera CCaress JGeiger JTXin WWIlardi AVerde FHayes SDPeverelli SPirisi AMosca LSilani VTaroni FMyers RMKirby JHeiman-Patterson TDKamel FKooyman MSabatelli MSideri RCeroni MBernard ELemasson GScholz SWGarcia-Redondo Avan den Berg LHMyllykangas LKenna KPBenatar MCamu WBarberis MGuy NHernandez DGTrojanowski JQMacGowan DJCannas AMcKenna-Yasek DSantarelli MBaas FPamphlett RShaw CEDay-Williams AGSiciliano GWuu JPani CBrice APugliatti MTrojsi FPuddu RSareen DCorrado LJones ALCalvo ARenton AEWallace MTicozzi NLattante SAppel SHMurphy NAManousakis GSpataro RKamalakaran SJackson CKeebler JGerhard GPisano FZody MCFemiano CWeber MBurns Tvan der Spek RDanel VEvani USVan Den Bosch LPoletti BClinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) ConsortiumMora Gde Carvalho MFrench ALS ConsortiumPolak Mvan Es MCirulli ETVeldink JCouthouis JNYGC ALS ConsortiumSimpson EZhang JRatti ABroach JRBoylan KBBedlack RSVolanti PFloris GTalbot KGenomic Translation for ALS Care (GTAC) ConsortiumRiva NCanosa ALanders JCostantino EMcMillan CKaye JFraenkel ETurner MRMiller TMGoutman SCudkowicz MVan Eijk KRQuerin GComi GPSimmons ZBrown RHThompson LMLanders JEKenna AOrrell RWConforti FLWimbish JRCavallaro SCarulli JPSchule RTedeschi GNath AChung WKVan der Spek RAColletti TMazzini Lvan Vugt JJFAKenna KBesson Gvan Rheenen WEaling JCorcia PPatsopoulos NASherman AMonsurro MRGotkine MTraynor BJZaitlen NAppel SRicci CMandich PCorbo MPinto SHeckmann JStatland JRademakers RLe Ber IWu GWang LSo YWang QFerrucci LRouleau GAKenna BJRavits JPulst SMStrom TMOrtu ERestagno GSimone ILWyman SShankaracharyaPardina JMKeagle PPulit SStone DJDrory VAnswer ALS FoundationMurru MRLaaksovirta HPhatnani HMarangi GSwenson AFratta POssola IDing JTranquilli SFilosto MMaiser SZatz MNicolas ALeNail AFini NShatunov ADubnau JMessina SMilia ACorti SCapasso MKrueger BJBrunetti MKing ABaloh RHVan Blitterswijk MChandran SBrown RfalseGenome-wide Analyses Identify KIF5A as a Novel ALS Gene.To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended surviva2018-01-01T00:00:00Z2018 Mar2026-04-29T03:53:33.169Z2019-06-06T19:11:40ZS-EPMC58678962956679310.1016/j.neuron.2018.02.027