A genome-wide association study meta-analysis identified 32 genomic loci, including 20 novel loci, significantly associated with calcific aortic valve stenosis.
Meta-Analysis (n=941,863)
Yes
This large-scale GWAS meta-analysis identifies 20 novel genomic loci for calcific aortic valve stenosis and highlights candidate causal genes such as TWIST1, providing potential novel therapeutic targets.
p-value: p=<5x10^-8
There is currently no medical therapy to prevent calcific aortic valve stenosis (CAVS). Multi-omics approaches could lead to the identification of novel molecular targets. Here, we perform a genome-wide association study (GWAS) meta-analysis including 14,819 cases among 941,863 participants of European ancestry. We report 32 genomic loci, among which 20 are novel. RNA sequencing of 500 human aortic valves highlights an enrichment in expression regulation at these loci and prioritizes candidate causal genes. Homozygous genotype for a risk variant near TWIST1, a gene involved in endothelial-mesenchymal transition, has a profound impact on aortic valve transcriptomics. We identify five genes outside of GWAS loci by combining a transcriptome-wide association study, colocalization, and Mendelian randomization analyses. Using cross-phenotype and phenome-wide approaches, we highlight the role of circulating lipoproteins, blood pressure and inflammation in the disease process. Our findings pave the way for the development of novel therapies for CAVS.
Thériault et al. (Sun,) conducted a meta-analysis in Calcific aortic valve stenosis (n=941,863). Genetic risk variants vs. Reference alleles was evaluated on Calcific aortic valve stenosis (p=<5x10^-8). A genome-wide association study meta-analysis identified 32 genomic loci, including 20 novel loci, significantly associated with calcific aortic valve stenosis.