Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.
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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.
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Acknowledgements: QUEBEC-CAVS was supported by the Heart and Stroke Foundation of Canada (G-19-0026386), the Canadian Institutes of Health Research (PJT – 153396, PJT – 162344) and the Fonds de recherche du Québec – Santé (278277). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The EPIC-Norfolk study has received funding from the Medical Research Council (MR/N003284/1 MC-UU_12015/1 and MC_UU_00006/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). The work of Estonian Genome Center, Univ. of Tartu was funded by the European Union through Horizon 2020 research and innovation programme under grants no. 810645 and 894987, through the European Regional Development Fund projects GENTRANSMED (2014-2020.4.01.15-0012), MOBERA5 (Norface Network project no 462.16.107), MOBEC008, MOBERA21 and Estonian Research Council Grants PUT1660 and PRG1291. We thank the research team at the cardiac surgical database and biobank of the Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval for their valuable assistance and all the participants. We thank the CARTaGENE study team and participants. We are grateful to all the participants who have been part of the EPIC-Norfolk study and to the many members of the study teams at the University of Cambridge who have enabled this research. We want to acknowledge the participants and investigators of Estonian biobank for their contribution. This work was carried out in part in the High Performance Computing Center of the University of Tartu. We thank all the UK Biobank participants and administration team. We want to acknowledge the participants and investigators of the FinnGen study.
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2041-1723
