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Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. We performed genetic analyses to uncover new genes associated with the disease. We identified a new susceptibility gene, named PALMD (palmdelphin), associated with CAVS and showed that the relationship is mediated by the expression level of the protein in the aortic valve. The UK Biobank data allowed to confirm the results observed in a local cohort of patients. The identification of this gene will help understand the cause of the disease and potentially develop new therapeutic options.