Abstract
Several vascular diseases including coronary artery disease, hypertension, stroke, and abdominal aortic aneurysm, have significant genetic underpinnings. Genome-wide association studies have unveiled many genetic loci associated with one or more of these diseases. However, the causative genes at most of these loci are yet to be determined, which hampers the translation of the genetic findings into a better understanding of the disease mechanisms and the identification of new therapeutic targets. Here, in an integrative functional genomics analysis of these loci, we identify a panel of likely causal genes, some of which are pleiotropic for more than one of these vascular diseases. Pooled CRISPR knockout screen analyses of these likely causal genes indicate that many of them influence vascular smooth muscle cell behaviour, and validation experiments of selected genes confirm that FES, BCAR1, CARF and SMARCA4 exert such effects. Further functional experiments focusing on FES, a pleiotropic gene for both coronary artery disease and hypertension, show that it modulates the expression of genes involved in vascular remodeling and that Fes knockout in mice promotes atherosclerosis as well as raises blood pressure. These findings provide an insight into the genetic basis of vascular diseases and inform targets for therapeutic development.
Data availability
The data that support the findings of this study are available from the corresponding author. The RNA-Seq data and H3K27ac HiChIP-seq data are available from Gene Expression Omnibus with the accession numbers GSE189300 and GSE282557. The DNA methylation data are available from ArrayExpress with the accession ID E-MTAB-15426. The proteomics data and phosphoproteomics data are available from MassIVE with the accession IDs PXD061984 [https://massive.ucsd.edu/ProteoSAFe/private-dataset.jsp?task=8660bf01bde54a50899b9126643cf52c] and PXD061992 [https://massive.ucsd.edu/ProteoSAFe/private-dataset.jsp?task=c1493e7d255a401b93782a307e5f0b64], respectively. Source data are provided in this paper.
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Acknowledgements
This work was funded by the British Heart Foundation [RG/16/13/32609, RG/19/9/34655, PG/16/9/31995, PG/18/73/34059, and SP/19/2/344612 to S.Y.), The National Medical Research Council of Singapore (MOH-001229 and MOH-001479 to S.Y.), and the National University of Singapore/National University Health System (NUHSRO/2022/004/Startup/01 to S.Y.). C.U.S. is a Leicester British Heart Foundation Accelerator Award (AA/18/3/34220) Research Fellow. D.G.M. is supported by the British Heart Foundation Research Excellence Award (RE/24/130031), the van Geest Foundation Heart and Cardiovascular Diseases Research Fund, and was awarded a BHF Accelerator Early Careers Researcher Interdisciplinary Fellowship and pump-priming funding from the Leicester British Heart Foundation Accelerator Award (AA/18/3/34220). This work falls under the portfolio of research conducted within the National Institute for Health Research Leicester Biomedical Research Centre and the Leicester BHF Centre of Research Excellence. This research used the ALICE High Performance Computing Facility at the University of Leicester.
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C.U.S., D.G.M., H.Z., and Y.Z. performed the analyses. D.G.M., C.A., P.G., L.T., D.S.S.S., H.Z., D.P.L., E.K., W.Y., J.C., R.C., K.E.H., C.G.A-N., H.L., M.J.D., P.Y.L, X.H., G.E.M., E.J.S., and G.D. performed the experiments. P.A.G. provided the mouse line. H.Y., R.S.Y.F., N.J.S., T.R.W., and S.Y. supervised the work. S.Y. wrote the paper. All the authors revised the manuscript, contributed with discussions and revisions and approved the final version of the manuscript.
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Solomon, C.U., McVey, D.G., Andreadi, C. et al. Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69273-8
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DOI: https://doi.org/10.1038/s41467-026-69273-8
