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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.

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