Login / Signup

Stroke genetics informs drug discovery and risk prediction across ancestries.

Aniket MishraRainer MalikTsuyoshi HachiyaTuuli JürgensonShinichi NambaDaniel C PosnerFrederick K KamanuMasaru KoidoQuentin Le GrandMingyang ShiYunye HeMarios K GeorgakisIlana CaroKristi KrebsYi-Ching LiawFelix C VauraKuang LinBendik Slagsvold WinsvoldVinodh SrinivasasainagendraLivia ParodiHee-Joon BaeGanesh ChauhanMichael R ChongLiisa TomppoRufus AkinyemiGennady V RoshchupkinNaomi HabibYon Ho JeeJesper Qvist ThomassenVida AbediJara Cárcel-MárquezMarianne NygaardHampton L LeonardChaojie YangEkaterina Yonova-DoingMaria J KnolAdam J LewisRenae L JudyTetsuro AgoPhillippe AmouyelNicole D ArmstrongMark K BakkerTraci M BartzDavid A BennettJoshua C BisConstance BordesSigrid BørteAnael CainPaul M RidkerKelly ChoZhengming ChenCarlos CruchagaJohn W ColePhilip Lawrence De JagerRafael de CidMatthias EndresLeslie Ecker FerreiraMirjam I GeerlingsNatalie C GascaVilmundur G GudnasonJun HataJing HeAlicia K HeathYuk-Lam HoAki Samuli HavulinnaJemma C HopewellHyacinth I HyacinthMichael InouyeMina A JacobChristina E JeonChristina JernMasahiro KamouchiKeith L KeeneTakanari KitazonoSteven J KittnerTakahiro KonumaAmit KumarPaul A LacazeLenore J LaunerKeon-Joo LeeKaido LepikJiang LiLiming LiAni W ManichaikulHugh S MarkusNicholas A MarstonThomas MeitingerBraxton D MitchellFelipe A MontellanoTakayuki MorisakiThomas H MosleyMike A NallsBørge Grønne NordestgaardMartin J O'DonnellYukinori OkadaN Charlotte Onland-MoretBruce OvbiageleAnnette PetersBruce M PsatyStephen S RichJonathan RosandMarc S SabatineRalph L SaccoDanish SaleheenElse Charlotte SandsetVeikko V SalomaaMuralidharan SargurupremrajMakoto SasakiClaudia L SatizabalCarsten O SchmidtAtsushi ShimizuNicholas L SmithKelly L SloaneYoichi SutohYan V SunKozo TannoSteffen TiedtTurgut TatlisumakNuria P Torres-AguilaHemant K TiwariDavid-Alexandre TrégouëtStella TrompetAnil Man TuladharAnne Tybjærg-HansenMarion van VugtRiina ViboShefali S VermaKerri L WigginsPatrik WennbergDaniel WooPeter W F WilsonHuichun XuQiong YangKyungheon Yoonnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullIona Y MillwoodChristian GiegerToshiharu NinomiyaHans J GrabeJohan Wouter JukemaIna L RissanenDaniel StrbianYoung Jin KimPei-Hsin ChenErnst MayerhoferJoanna M M HowsonMarguerite R IrvinHieab H H AdamsSylvia Wassertheil-SmollerKaare ChristensenMohammad Arfan IkramTatjana RundekBradford B WorrallG Mark LathropMoeen RiazEleanor M SimonsickJanika KõrvPaulo Henrique Condeixa de FrançaRamin ZandKameshwar PrasadRuth Frikke-SchmidtFrank-Erik de LeeuwThomas LimanKarl Georg HaeuslerYnte M RuigrokPeter Ulrich HeuschmannW T LongstrethKeum Ji JungLisa BastaracheGuillaume ParéScott M DamrauerDaniel I ChasmanJerome I RotterChristopher D AndersonJohn-Anker ZwartTeemu J NiiranenMyriam FornageYung-Po LiawSudha SeshadriIsrael Fernández-CadenasRobin G WaltersChristian T RuffMayowa Ojo OwolabiJennifer E HuffmanLili A MilaniYoichiro KamataniMartin DichgansStephanie Debette
Published in: Nature (2022)
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Keyphrases