Rare and Common Variants Uncover the Role of the Atria in Coarctation of the Aorta

Coarctation of the aorta (CoA) and bicuspid aortic valve (BAV) often cooccur and are genetically linked congenital heart defects (CHD). While CoA is thought to have a hemodynamic origin from ventricular dysfunction, we provide evidence pointing to atrial hemodynamics based on investigating the genetic etiology of CoA. Previous studies have shown a rare MYH6 variant in an Icelandic cohort, and two common deletions in the protocadherin α cluster (PCDHA delCNVs) are significantly associated with CoA and BAV. Here, analysis of a non-Icelandic white CHD cohort (n = 166) recovered rare MYH6 variants in 10.9% of CoA and 32.7% of BAV/CoA patients, yielding odds ratios of 18.6 (p = 2.5 × 10−7) and 20.5 (p = 7.4 × 10−5) for the respective association of MYH6 variants with CoA and BAV/CoA. In combination with the PCHDA delCNVs, they accounted for a third of CoA cases. Gene expression datasets for the human and mouse embryonic heart showed that both genes are predominantly expressed in the atria, not the ventricle. Moreover, cis-eQTLs analysis showed the PCHDA delCNV is associated with reduced atrial expression of PCHDA10, a gene in the delCNV interval. Together, these findings showed that PCDHA/MYH6 variants account for a substantial fraction of CoA cases. An atrial rather than ventricular hemodynamic model for CoA is indicated, consistent with the known early atrial functional dominance of the human embryonic heart.