Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease.

Abstract

Population based studies demonstrate strong familial recurrence of cardiac malformations particularly for individuals affected with a specific class of CHD, left-ventricular outflow tract (LVOT) obstruction. Recently we linked 99 lead variants across 71 loci to diameter of the ascending aorta derived from MRI measurements across multiple ethnicities in the UK Biobank. Using these data we created a polygenic risk score capturing ascending aortic diameter (PRSAoD) Among 2,594 individuals with CHD; a decrease by one standard deviation in PRSAoD was associated with an increased risk of congenital LVOT (OR=1.14[1.03-1.26], p=0.014) but not with other subtypes of CHD. Using Mendelian Randomization we observed strong evidence of a causal effect where inheritance of a smaller diameter of the ascending aorta corresponded to an increase in risk for congenital LVOT (p_IVW = 0.008). Our data may suggest that genetic determinants of a smaller ascending aorta act during early development to disturb blood flow through left-sided structures to increasing the risk of LVOT CHD, which is consistent with experimental evidence and the flow, no grow paradigm in the formation of the left ventricular outflow tract.