Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction
Aeron Small, Ta‐Yu Yang, Shinsuke Itoh, Sébastien Thériault, Line Dufresne, Ryo Kurosawa, Issei Komuro, Koichi Matsuda, Ha My T. Vy, Eric Farber‐Eger, Lauren Lee Shaffer, Kristin M. Boulier, Kristin Corey, Megan E. Ramaker, Fabien Laporte, Jean‐Jacques Schott, Solena Le Scouarnec, Sasha A. Singh, Abhijeet R. Sonawane, Harry Smith, Nicholas Rafaels, Jonas Ghouse, Anna Axelsson Raja, Sisse Rye Ostrowski, Erik Sørensen, Christina Mikkelsen, Ole Birger Pedersen, Christian Erikstrup, Henrik Ullum, Garðar Sveinbjörnsson, Daníel F. Guðbjartsson, Erik Abner, Jiwoo Lee, Andrea Ganna, Ulrike Nowak‐Göttl, Sarah Finer, David A. van Heel, Johannes Schumacher, Carlo Maj, Baravan Al‐Kassou, Georg Nickenig, Teresa Trenkwalder, Martina Dreßen, Markus Krane, Markus M. Nöthen, Marta R. Moksnes, Ben 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, André Franke, Klaus Peter Berger, Christian T. Ruff, Giorgio Melloni, Frederick Kamanu, Kaoru Ito, Ron Do, Ruth J. F. Loos, Heribert Schunkert, Quinn S. Wells, Svati H. Shah, Thierry Le Tourneau, David Messika–Zeitoun, Christopher R. Gignoux, Henning Bundgaard, Susanna C. Larsson, Karl Michaëlsson, Hilma Hólm, Anna Helgadóttir, Tonu Esko, David A. van Heel, Patrick Mathieu, Nilesh J. Samani, J. G. Smith, Stefan Söderberg, Daniel J. Rader, Nicholas Marston, Marc S. Sabatine, Bogdan Paşaniuc, Kelly Cho, Peter W.F. Wilson, Christopher J. O’Donnell, Kāri Stefánsson, Yohan Bossé, Elena Aïkawa, James C. Engert, Gina M. Peloso
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.