Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases
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.
Authors
- Charles U. Solomon (ORCID: https://orcid.org/0000-0002-6462-3384)
- G E Morris
- Catherine Andreadi
- Peter A. Greer (ORCID: https://orcid.org/0000-0002-7809-5105)
- P. Gong
- Lenka Turner
- Jiapeng Chu (ORCID: https://orcid.org/0000-0001-9171-2764)
- Emma J. Stringer
- Chukwuemeka George Anene-Nzelu (ORCID: https://orcid.org/0000-0003-4973-418X)
- Heng Zhang (ORCID: https://orcid.org/0000-0002-0103-2173)
- Yanhong Zhang (ORCID: https://orcid.org/0000-0003-4412-5641)
- Hui Li (ORCID: https://orcid.org/0000-0002-7879-1792)
- Gillian Douglas (ORCID: https://orcid.org/0000-0002-9090-5326)
- David G. McVey (ORCID: https://orcid.org/0000-0002-6402-2546)
- Tom R. Webb
- Elisavet Karamanavi
- D Lee
- Matthew Denniff
- R Foo
- Haojie Yu
- Dedrick S. S. Song
- Runji Chen
- Nilesh J. Samani
- Shu Ye
- Wei Yang
- Xiaoxin Huang
- Kim E. Haworth
- Peter Y. Li
Institutions
- Centre for Human Genetics (GB)
- University of Leicester (GB)
- National University of Singapore (SG)
- Queen's University (CA)
- Montreal Heart Institute (CA)
- British Heart Foundation (GB)
- Shantou University (CN)
- National Institute for Health and Care Research (GB)
- University of Oxford (GB)
- Gannan Medical University (CN)
- First Affiliated Hospital of Shantou University Medical College (CN)
- Shantou University Medical College (CN)
- NIHR Leicester Biomedical Research Centre (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1038/s41467-026-69273-8
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute for Health and Care Research
- British Heart Foundation
- University of Leicester
- National University of Singapore
- National University Health System
- Medical Research Council
- National Medical Research Council
- NIHR Leicester Biomedical Research Centre