Genomic 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 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.

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Publication Details

Journal
Nature Genetics
Published
2025-12-19
DOI
https://doi.org/10.1038/s41588-025-02417-6
Citations
3
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
5.45

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article

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

Peter W.F. Wilson, Anna Axelsson Raja, Lauren Lee Shaffer, Christina Mikkelsen et al.
3 citations
Nature Genetics
Genetic Associations and Epidemiology
5.45
article

Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction

Peter W.F. Wilson, Anna Axelsson Raja, Lauren Lee Shaffer, Christina Mikkelsen, Heribert Schunkert, Erik Abner, J. G. Smith, Satoshi Koyama, Klaus Peter Berger, Nicholas Rafaels, Sasha A. Singh, Ruth J. F. Loos, Christian T. Ruff, Henrik Ullum, David A. van Heel, Erik Sørensen, Kāri Stefánsson, Svati H. Shah, Frederick Kamanu, Eric Farber‐Eger, Yunfeng Ruan, Solena Le Scouarnec, Jean‐Jacques Schott, Carlo Maj, George Thanassoulis, Tonu Esko, Gina M. Peloso, Jiwoo Lee, Martina Dreßen, Teresa Trenkwalder, Giorgio Melloni, Thierry Le Tourneau, Harry Smith, Lincoln Nadauld, Daníel F. Guðbjartsson, Stefan Söderberg, Pradeep Natarajan, Kelly Cho, Ha My T. Vy, Henning Bundgaard, Ole Birger Pedersen, Aeron Small, Baravan Al‐Kassou, Quinn S. Wells, Jonas Ghouse, Bogdan Paşaniuc, Issei Komuro, David Messika‐Zeitoun, Sisse Rye Ostrowski, Johan Ljungberg, Elena Aïkawa, Sébastien Thériault, Daniel James Rader, Line Dufresne, Shinsuke Itoh, Abhijeet R. Sonawane, Kristin M. Boulier, Sarah Finer, Patrick Mathieu, Koichi Matsuda, André Franke, Fabien Laporte, Andrea Ganna, Radosław Dębiec, Christian Erikstrup, Ron Do, Kristin Corey, Yohan Bossé, Margaret Sunitha Selvaraj, Ryo Kurosawa, Michael G. Levin, Megan E. Ramaker, James C. Engert, Ben Michael Brumpton, Johannes Schumacher, Karl Michaëlsson, Anna Helgadóttir, Scott M. Damrauer, Peter S. Braund, Markus Krane, Hilma Hólm, Christopher R. Gignoux, Stacey Knight, Olle Melander, Kirk U. Knowlton, Marta R. Moksnes, Susanna C. Larsson, Markus M. Nöthen, Nicholas Marston, Garðar Sveinbjörnsson, Rohan Bhukar, Nilesh J. Samani, Christopher P. Nelson, Ta‐Yu Yang, Kaoru Ito, Tomasz Czuba, Marc S. Sabatine, Christopher J. O’Donnell, Ulrike Nowak‐Göttl, Georg Nickenig, Muntaser D. Musameh
article en
3 citations

Abstract

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.

Nature GeneticsVol. 58(1)
Statens Serum Institut (DK), Broad Institute (US), Intermountain Healthcare (US), Human Genome Sciences (United States) (US), Boston University (US), Uppsala University (SE), University of Copenhagen (DK), Brigham and Women's Hospital (US), Centre National de la Recherche Scientifique (FR), deCODE Genetics (Iceland) (IS), University of Helsinki (FI), University of Bonn (DE), Harvard University (US), University of Leicester (GB), University of Ottawa (CA), Inserm (FR), Chiba University (JP), Philipps University of Marburg (DE), University of California, Los Angeles (US), Queen Mary University of London (GB), Duke University (US), Lund University (SE), Norwegian University of Science and Technology (NO), Kyoto University (JP), University of Münster (DE), University Hospital Bonn (DE), Sahlgrenska University Hospital (SE), Novo Nordisk Foundation (DK), Ronald Reagan UCLA Medical Center (US), VA Boston Healthcare System (US), McGill University Health Centre (CA), Glenfield Hospital (GB), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Atlanta Medical Center (US), Karolinska Institutet (SE), Christian-Albrechts-Universität zu Kiel (DE), Yale University (US), Massachusetts General Hospital (US), Clinical Research Institute (US), Harvard–MIT Division of Health Sciences and Technology (US), St Olav's University Hospital (NO), German Centre for Cardiovascular Research (DE), Philadelphia VA Medical Center (US), Institute for Molecular Medicine Finland (FI), Institut universitaire de cardiologie et de pneumologie de Québec (CA), Skåne University Hospital (SE), Institut du Thorax (FR), Deutsches Herzzentrum München (DE), RIKEN Center for Integrative Medical Sciences (JP), Atlanta VA Medical Center (US), Zealand University Hospital Køge (DK), Center for Systems Biology (US), Thrombolysis in Myocardial Infarction Study Group (US), NIHR Leicester Biomedical Research Centre (GB), Université Laval (CA), McGill University (CA), University of Colorado Anschutz Medical Campus (US), University of Tartu (EE), Technical University of Munich (DE), The University of Tokyo (JP), International University of Health and Welfare (JP), University of Pennsylvania (US), Vanderbilt University Medical Center (US), Umeå University (SE), Nantes Université (FR), Icahn School of Medicine at Mount Sinai (US)
Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research
Openalex Percentile: Top 4%
Genetic Associations and Epidemiology
5.45
DOIOpen Access PDFOpenAlex
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