Phenome-wide analyses establish a specific association between aortic valve PALMD expression and calcific aortic valve stenosis

Calcific aortic valve stenosis (CAVS) is a frequent heart disease with significant morbidity and mortality. Recent genomic studies have identified a locus near the gene PALMD (palmdelphin) strongly associated with CAVS. Here, we show that genetically-determined expression of PALMD in the aortic valve is inversely associated with CAVS, with a stronger effect in women, in a meta-analysis of two large cohorts totaling 2359 cases and 350,060 controls. We further demonstrate the specificity of this relationship by showing the absence of other significant association between the genetically-determined expression of PALMD in 9 tissues and 852 phenotypes. Using genome-wide association studies meta-analyses of cardiovascular traits, we identify a significant colocalized positive association between genetically-determined expression of PALMD in four non-cardiac tissues (brain anterior cingulate cortex, esophagus muscularis, tibial nerve and subcutaneous adipose tissue) and atrial fibrillation. The present work further establishes PALMD as a promising molecular target for CAVS.
Zhonglin Li et al. perform phenome-wide analyses to explore the genetic association between the locus near PALMD and calcific aortic valve stenosis (CAVS). Using previously reported aortic valve expression data and genotypes from large cohorts, they find a strong and specific association between genetically-determined PALMD expression in the aortic valve and CAVS as well as a novel association with atrial fibrillation in non-cardiac tissues.