A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis

Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease with no drug that can stop or delay its progression. Elucidating the genetic factors underpinning CAVS is an urgent priority to find new therapeutic targets 1 . Major landmarks in genetics of CAVS include the discoveries of NOTCH1 2 and LPA 3 . However, genetic variants in these genes accounted for a small number of cases and low population-attributable risk. Here we mapped a new susceptibility locus for CAVS on chromosome 1p21.2 and identified PALMD (palmdelphin) as the causal gene. PALMD was revealed using a transcriptome-wide association study (TWAS) 4 , which combines a genome-wide association study (GWAS) of 1,009 cases and 1,017 ethnically-matched controls with the first large-scale expression quantitative trait loci (eQTL) mapping study on human aortic valve tissues (n=233). The CAVS risk alleles and increasing disease severity were both associated with lowered mRNA expression levels of PALMD in valve tissues. The top variant explained up to 12.5% of the population-attributable risk and showed similar effect and strong association with CAVS (P=1.53 × 10 −10 ) in UK Biobank comparing 1,391 cases and 352,195 controls. The identification of PALMD as a susceptibility gene for CAVS provides new insights about the genetic nature of this disease and opens new avenues to investigate its etiology and develop much-needed therapeutic options.