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

• Published in: Nature communications Vol. 9; no. 1; pp. 988 - 8
• Main Authors: Thériault, Sébastien, Gaudreault, Nathalie, Lamontagne, Maxime, Rosa, Mickael, Boulanger, Marie-Chloé, Messika-Zeitoun, David, Clavel, Marie-Annick, Capoulade, Romain, Dagenais, François, Pibarot, Philippe, Mathieu, Patrick, Bossé, Yohan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 45/61; 631/208/191/2018; 631/208/205/2138; 692/699/75/591; Aortic valve; Aortic Valve - pathology; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - pathology; Biobanks; Calcinosis - genetics; Calcinosis - pathology; Cardiovascular disease; Cardiovascular diseases; Coronary artery disease; Coronary vessels; Disease Progression; Etiology; Gene expression; Gene mapping; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Heart diseases; Humanities and Social Sciences; Humans; Membrane Proteins - genetics; multidisciplinary; Rheumatic heart disease; Science; Science (multidisciplinary); Stenosis; Transcriptome - genetics; United Kingdom > UK
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03260-6

Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues ( n  = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS ( P  = 1.53 × 10 −10 ) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options. Progressive remodeling and calcification of the aortic valve leads to calcific aortic valve stenosis (CAVS) and, ultimately, heart failure. In a combined GWAS and TWAS approach, Thériault et al. identify PALMD as a candidate causal gene for CAVS, which is further supported by Mendelian randomization.