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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 score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of\n                    <jats:italic>CMKLR1<\/jats:italic>\n                    and\n                    <jats:italic>LTBP4<\/jats:italic>\n                    in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor \u03b2 signaling in AS.\n                  <\/jats:p>","DOI":"10.1038\/s41588-025-02417-6","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T10:01:42Z","timestamp":1766138502000},"page":"57-66","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction"],"prefix":"10.1038","volume":"58","author":[{"given":"Aeron 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M.K. is a physician proctor and a member of the medical advisory board for JOMDD, a physician proctor for Peter Duschek, a medical consultant for EVOTEC and Moderna and has received speakers\u2019 honoraria from Medtronic and Terumo. S.M.D. has research support from Renalytix and Novo Nordisk. R.J.F.L. is a consultant for Eli Lilly and Novo Nordisk. S.S. receives speaker\u2019s honoraria and is on the scientific board for Johnson & Johnson. C.J.O. is employed by Novartis Pharmaceuticals. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech\/Roche and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech\/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. G.T. has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics and Silence, all unrelated to the current work. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}