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Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction
Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA.;Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Cardiovasc Dis Initiat, Cambridge, MA USA.;VA Boston Healthcare Syst, Dept Med, Div Cardiol, Boston, MA USA..
McGill Univ, Hlth Ctr & Res Inst, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Kyoto Univ, Kyoto McGill Int Collaborat Sch Genom Med, Grad Sch Med, Kyoto, Japan..ORCID iD: 0000-0002-5379-5340
Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA.;Harvard Med Sch, Brigham & Womens Hosp, Ctr Interdisciplinary Cardiovasc Sci, Boston, MA USA..ORCID iD: 0000-0001-9567-8188
Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.;Univ Laval, Dept Mol Biol Med Biochem & Pathol, Quebec City, PQ, Canada..
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2026 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 58, p. 57-66Article in journal (Refereed) Published
Abstract [en]

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 score for AS. Finally, we performed gene silencing experiments targeting biologically relevant genes identified by our GWAS. Silencing of CMKLR1 and LTBP4 in human valvular interstitial cells substantially decreased mineralization, implicating a role for polyunsaturated fatty acids and transforming growth factor β signaling in AS.
Place, publisher, year, edition, pages
Springer Nature, 2026. Vol. 58, p. 57-66
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Medical Genetics and Genomics Cardiology and Cardiovascular Disease
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URN: urn:nbn:se:uu:diva-593199DOI: 10.1038/s41588-025-02417-6ISI: 001642743700001PubMedID: 41419686Scopus ID: 2-s2.0-105027688550OAI: oai:DiVA.org:uu-593199DiVA, id: diva2:2083893
Available from: 2026-07-03 Created: 2026-07-03 Last updated: 2026-07-03Bibliographically approved

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Yang, Ta-YuItoh, ShinsukeDufresne, LineMatsuda, KoichiFarber-Eger, Eric H.Erikstrup, ChristianUllum, HenrikGanna, AndreaMaj, CarloLoos, Ruth J. F.Larsson, Susanna C.Michaëlsson, KarlSmith, J. GustavCho, Kelly
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