Multitrait analyses identify genetic variants associated with aortic valve function and aortic stenosis risk.
Authors
Affiliations (18)
Affiliations (18)
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
- University of Minnesota Medical School, Minneapolis, MN, USA.
- Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Center, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.
- Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
- Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
- Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Cardiology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA.
- Harvard Medical School, Boston, MA, USA.
- Thoracic Aortic Center, Massachusetts General Hospital, Boston, MA, USA.
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA. [email protected].
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. [email protected].
Abstract
The genetic influences on normal aortic valve function and their impact on aortic stenosis risk are of substantial interest. We used deep learning to measure peak velocity, mean gradient and aortic valve area from magnetic resonance imaging and conducted genome-wide association studies (GWAS) in 59,571 participants in the UK Biobank. Incorporating the aortic valve measurement GWAS with aortic stenosis GWAS using multitrait analysis of GWAS (MTAG), we identified 166 distinct loci (134 with aortic valve traits, 134 with aortic stenosis and 166 unique loci across all GWAS), including PCSK9 and LDLR. The MTAG aortic stenosis PGS was associated with aortic stenosis in All of Us (hazard ratio (HR) = 3.32 for top 5% versus all others, P = 8.8 × 10<sup>-22</sup>) and Mass General Brigham Biobank (HR = 2.76, P = 7.8 × 10<sup>-15</sup>). Using Mendelian randomization, we found evidence supporting a potential causal role for Lp(a) and LDL on aortic valve function. These findings have implications for the early pathogenesis of aortic stenosis and suggest modifiable pathways as targets for preventive therapy.