Integrative functional genomics analysis identifies pleiotropic genes for vascular diseases.

Area of Science:

• Genetics
• Cardiovascular Diseases
• Genomics

Background:

• Vascular diseases like coronary artery disease, hypertension, stroke, and abdominal aortic aneurysm have known genetic links.
• Genome-wide association studies (GWAS) have identified numerous genetic loci associated with these diseases.
• Identifying causative genes at these loci is crucial for understanding disease mechanisms and developing therapies.

Purpose of the Study:

• To identify likely causal genes underlying common vascular diseases through integrative functional genomics.
• To investigate the role of these genes in vascular smooth muscle cell behavior and disease pathogenesis.
• To explore the pleiotropic effects of identified genes on multiple vascular conditions.

Main Methods:

• Integrative functional genomics analysis of GWAS loci associated with vascular diseases.
• Pooled CRISPR knockout screens to assess gene function in vascular smooth muscle cells.
• In vivo validation experiments, including gene knockout in mice, to confirm functional effects.

Main Results:

• A panel of likely causal genes for vascular diseases was identified, with some showing pleiotropic effects.
• CRISPR screens revealed that many identified genes impact vascular smooth muscle cell behavior.
• Validation confirmed FES, BCAR1, CARF, and SMARCA4 influence vascular cell function.
• FES was identified as a pleiotropic gene for coronary artery disease and hypertension, modulating vascular remodeling genes.
• Fes knockout mice exhibited accelerated atherosclerosis and elevated blood pressure.

Conclusions:

• This study provides insights into the genetic architecture of vascular diseases.
• Identified genes, particularly FES, represent potential therapeutic targets for cardiovascular conditions.
• Understanding gene function in vascular smooth muscle cells is key to deciphering disease mechanisms.