biostudies-literatureSmall AMNHLBI NIH HHS57-66https://www.ebi.ac.uk/biostudies/studies/S-EPMC12807872biostudies-literatureUnknown58(1)Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk Nature geneticsGenomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction.PMC12807872R01 HL127564Bundgaard HSchott JJMelander OMathieu PWells QSGenes & Health Research TeamDamrauer SMMoksnes MRThanassoulis GMatsuda KKomuro IEsko TBoulier KMGhouse JGignoux CNelson CPMarston NAAl-Kassou BDebiec RUllum HSingh SABerger KShah SHvan Heel DAHolm HDo RMelloni GEMErikstrup CLee JMichaelsson KFranke AVy HMTNadauld LKnight SLoos RJFLarsson SCFarber-Eger EHSmith JGFiner SSoderberg SKrane MSveinbjornsson GKamanu FKKurosawa RSelvaraj MSNickenig GDBDS Genomic ConsortiumGanna ABrumpton BMWilson PWFMessika-Zeitoun DOstrowski SRPedersen OBEngert JCShaffer LLRuff CTCzuba TRuan YBraund PSKoyama SLjungberg JStefansson KTrenkwalder TTheriault SNothen MMNowak-Gottl URafaels NSorensen EColorado Center for Personalized MedicineIto KSchumacher JSchunkert HPeloso GMLevin MGSmith HADufresne LRamaker MEAbner ESamani NJPasaniuc BAikawa EMaj CLaporte FSmall AMSabatine MSCorey KMItoh SRader DJDreβen MLe Tourneau TBhukar RCho KEstonian Biobank Research TeamMikkelsen CSonawane ARNatarajan PO'Donnell CJYang TYHelgadottir AKnowlton KULe Scouarnec SGudbjartsson DFRaja AAMusameh MDBosse YfalseGenomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction.Aortic stenosis (AS) is a common valvular heart disease and has no pharmacological therapies. We performed a multi-ancestry genome-wide association meta-analysis of 86,864 AS cases among 2,853,408 individuals, discovering 241 autosomal independent risk loci and 3 X chromosome risk loci. We additionally performed sex-stratified and ancestry-stratified genome-wide association studies (GWASs), identifying an additional 5 sex-specific risk loci, 11 risk loci in European ancestry individuals and 1 risk locus in African ancestry individuals. We also performed a transcriptome-wide association study using expression quantitative trait loci from human aortic valves, discovering 54 new genes for which genetically predicted expression influences the risk of AS. We then generated a new polygenic risk 2026-01-01T00:00:00Z2026 Jan2026-07-15T14:36:13.063Z2026-07-06T03:08:30.35ZS-EPMC128078724141968610.1038/s41588-025-02417-6