The Genetic Determinants of Aortic Distension

As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous blood delivery to peripheral arteries. Distension during systole and recoil during diastole conserves ventricular energy and is enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and prematurely in vascular disease. To discover genetic determinants of aortic distensibility we trained a deep learning model to quantify aortic size throughout the cardiac cycle and calculate aortic distensibility and aortic strain in 42,342 participants in the UK Biobank with available cardiac magnetic resonance imaging. In up to 40,028 participants with genetic data, common variant analysis identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were specific to strain or distensibility and were not identified in a thoracic aortic diameter GWAS within the same samples. Loci associated with both aortic diameter and aortic strain or distensibility demonstrated a consistent, inverse directionality. Transcriptome-wide analyses, rare-variant burden tests, and analyses of gene expression in single nucleus RNA sequencing of human aorta were performed to prioritize genes at individual loci. Loci highlighted multiple genes involved in elastogenesis, matrix degradation, and extracellular polysaccharide generation. Characterization of the genetic determinants of aortic function may provide novel targets for medical intervention in aortic disease.