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Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction
Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, MA, Boston, United States; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, MA, Cambridge, United States; Division of Cardiology, Department of Medicine, VA Boston Healthcare System, MA, Boston, United States.
McGill University Health Centre and Research Institute, QC, Montréal, Canada; McGill University, QC, Montréal, Canada; Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, MA, Boston, United States; Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School, MA, Boston, United States.
Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval, QC, Quebec City, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, QC, Quebec City, Canada.
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2026 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 58, no 1, 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
Nature Publishing Group, 2026. Vol. 58, no 1, p. 57-66
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Medical Genetics and Genomics
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URN: urn:nbn:se:umu:diva-249009DOI: 10.1038/s41588-025-02417-6ISI: 001642743700001PubMedID: 41419686Scopus ID: 2-s2.0-105027688550OAI: oai:DiVA.org:umu-249009DiVA, id: diva2:2033964
Available from: 2026-01-30 Created: 2026-01-30 Last updated: 2026-01-30Bibliographically approved

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Ljungberg, JohanSöderberg, Stefan

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