Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Mar 2024
18 Mar 2024
Historique:
received:
28
06
2023
accepted:
05
03
2024
medline:
18
3
2024
pubmed:
18
3
2024
entrez:
18
3
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38494474
doi: 10.1038/s41467-024-46639-4
pii: 10.1038/s41467-024-46639-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2407Subventions
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : PJT-162344
Organisme : Heart and Stroke Foundation of Canada (Heart and Stroke Foundation)
ID : G-19-0026386
Informations de copyright
© 2024. The Author(s).
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