A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis.
Sébastien ThériaultNathalie GaudreaultMaxime LamontagneMickael RosaMarie-Chloé BoulangerDavid Messika-ZeitounMarie-Annick ClavelRomain CapouladeFrançois DagenaisPhilippe PibarotPatrick MathieuYohan BossePublished in: Nature communications (2018)
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.
Keyphrases
- aortic valve
- transcatheter aortic valve replacement
- genome wide
- aortic stenosis
- transcatheter aortic valve implantation
- aortic valve replacement
- gene expression
- copy number
- dna methylation
- single cell
- mitral valve
- heart failure
- rna seq
- coronary artery disease
- cross sectional
- transcription factor
- genome wide identification
- pluripotent stem cells
- high density