Researchers map genetic architecture of vascular ageing using genomic structural equation modeling

A study mapping the shared genetic architecture of five vascular ageing traits has identified 249 genomic risk loci and highlighted SASP pathways, providing a genomic framework that could inform therapeutic targets for age-related cardiovascular decline.

Researchers applied genomic structural equation modeling (Genomic SEM) to GWAS summary statistics for five vascular-ageing traits in European-ancestry populations: arterial stiffness, pulse pressure, carotid artery thickness, coronary artery calcification, and carotid plaque.

The common-factor model demonstrated strong fit statistics, with a Comparative Fit Index (CFI) of 0.998 and Standardized Root Mean Square Residual (SRMR) of 0.047.

The multivariate GWAS identified 372 independent lead SNPs across 249 genomic risk loci, which included three loci newly implicated in vascular ageing.

Bayesian fine-mapping and transcriptomic prioritization (TWAS) identified 49 high-confidence causal SNPs and 69 putative causal genes, with CDH13, FES, and CCN3 emerging as key convergent genes across multiple lines of genomic evidence.

Pathway and cell-type enrichment analyses highlighted the senescence-associated secretory phenotype (SASP), circulatory system processes, and extracellular matrix organization as central biological mechanisms, implicating endothelial cells, smooth muscle cells, fibroblasts, and monocytes/macrophages as key cellular substrates.

Vascular ageing is a central systemic driver of age-related cardiovascular morbidity, and defining its shared genetic architecture allows researchers to look beyond isolated symptoms like arterial stiffness toward a unified biological process.

The convergence on CDH13, FES, and CCN3 points to specific molecular targets involved in endothelial adhesion, vascular inflammation, and extracellular matrix remodeling.

The statistical enrichment of the SASP pathway provides genetic evidence linking cellular senescence to systemic vascular degradation.

The genetic confirmation of the SASP pathway's role in vascular ageing supports the therapeutic hypothesis of longevity biotechnology companies targeting cellular senescence and tissue rejuvenation.

The prioritization of specific genes like CDH13, FES, and CCN3 provides early-stage targets for preclinical validation, potentially expanding the pipeline of therapeutic candidates for age-related vascular diseases.

Preclinical validation of the identified causal genes (CDH13, FES, CCN3) in model organisms to confirm their roles in arterial stiffening and plaque formation.

The potential translation of these multivariate findings into polygenic risk scores capable of predicting vascular ageing trajectories in clinical populations.