A transcriptome-wide association study identifiesPALMDas a susceptibility gene for calcific aortic valve stenosis

AbstractCalcific 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 targets1. Major landmarks in genetics of CAVS include the discoveries ofNOTCH12andLPA3. 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 identifiedPALMD(palmdelphin) as the causal gene.PALMDwas 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 ofPALMDin 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 ofPALMDas 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.