Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation

• Published in: Nature communications Vol. 15; no. 1; p. 2407
• Main Authors: Thériault, Sébastien, Li, Zhonglin, Abner, Erik, Luan, Jian’an, Manikpurage, Hasanga D., Houessou, Ursula, Zamani, Pardis, Briend, Mewen, Boudreau, Dominique K., Gaudreault, Nathalie, Frenette, Lily, Argaud, Déborah, Dahmene, Manel, Dagenais, François, Clavel, Marie-Annick, Pibarot, Philippe, Arsenault, Benoit J., Boekholdt, S. Matthijs, Wareham, Nicholas J., Esko, Tõnu, Mathieu, Patrick, Bossé, Yohan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 45/91; 49/39; 631/208/199; 631/208/205/2138; 692/4019/592/2727; Aorta; Aortic stenosis; Aortic valve; Aortic Valve - metabolism; Aortic Valve - pathology; Aortic Valve Stenosis - genetics; Blood circulation; Blood pressure; Calcinosis; Gene loci; Gene sequencing; Genes; Genome-wide association studies; Genome-Wide Association Study; Genomic analysis; Genomics; Genotypes; Heart valves; Humanities and Social Sciences; Humans; Lipoproteins; multidisciplinary; Phenotypes; Rheumatic heart disease; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Stenosis; Transcriptomes; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46639-4

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. Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1 , a gene involved in endothelial-mesenchymal transition.