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

Sébastien Thériault (), Zhonglin Li, Erik Abner, Jian’an Luan, Hasanga D. Manikpurage, Ursula Houessou, Pardis Zamani, Mewen Briend, Dominique K. Boudreau, Nathalie Gaudreault, Lily Frenette, Déborah Argaud, Manel Dahmene, François Dagenais, Marie-Annick Clavel, Philippe Pibarot, Benoit J. Arsenault, S. Matthijs Boekholdt, Nicholas J. Wareham, Tõnu Esko, Patrick Mathieu and Yohan Bossé
Additional contact information
Sébastien Thériault: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Zhonglin Li: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Erik Abner: University of Tartu
Jian’an Luan: University of Cambridge
Hasanga D. Manikpurage: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Ursula Houessou: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Pardis Zamani: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Mewen Briend: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Dominique K. Boudreau: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Nathalie Gaudreault: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Lily Frenette: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Déborah Argaud: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Manel Dahmene: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
François Dagenais: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Marie-Annick Clavel: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Philippe Pibarot: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Benoit J. Arsenault: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
S. Matthijs Boekholdt: University of Amsterdam
Nicholas J. Wareham: University of Cambridge
Tõnu Esko: University of Tartu
Patrick Mathieu: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval
Yohan Bossé: Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46639-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46639-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46639-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().