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

Nature genetics

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

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.

© 2025. The Author(s).

PMID: 41419686

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