Integrative multivariate genomic analysis reveals shared genetic determinants and druggable targets for vascular...

Vascular calcification (VC), characterized by calcium deposition in arterial walls, is a major risk factor for cardiovascular morbidity and mortality. While genome-wide association studies (GWAS) have identified susceptibility loci for specific vascular beds, such as coronary artery calcification (CAC) and abdominal aortic calcification (AAC), single-phenotype studies may overlook pleiotropic variants. This study aims to elucidate the shared genetic architecture of CAC and AAC and translate these findings into biological insights and potential therapeutic targets.

We performed a multivariate genome-wide analysis integrating summary statistics for CAC and AAC from individuals of European ancestry. To prioritize candidate genes, we applied four complementary mapping strategies, including positional mapping, multivariate set-based association test, transcriptome-wide association study, and multi-marker analysis of genomic annotation. Findings were further characterized using tissue-specific expression profiling, Gene Ontology enrichment, and cell-type specificity analysis. Therapeutic potential and safety were subsequently evaluated using OpenTargets for druggability assessment and phenome-wide association studies (PheWAS) to assess horizontal pleiotropy. Finally, experimental validation was conducted to verify the genetic findings.

The multivariate analysis identified seven genome-wide significant loci. Cross-referencing the four gene-mapping strategies highlighted a consensus set of robust candidate genes, with CDKN2B supported by all methods, and strong multi-method support for ADAMTS7, PHACTR1, and MORF4L1. Pathway analysis identified lipid homeostasis and cell cycle regulation as key functional modules. Cell-type specificity analysis demonstrated that candidate genes were enriched in endothelial cells. Druggability assessments identified HDAC9 as a target for approved drugs potentially repurposed for VC, while PheWAS results suggested a predicted lack of severe genetic pleiotropy for most candidates, with the notable exception of CDKN2A, which showed associations with neoplasms. Quantitative real-time PCR confirmed significantly altered expression of most candidate genes, including ADAMTS7, CDKN2A, CDKN2B, CXCL12, FHL5, HDAC9, MORF4L1, PDGFD, and PHACTR1, in the experimental group.

This study demonstrates that CAC and AAC share a substantial genetic basis, reinforcing the concept of VC as a systemic pathological process driven by common mechanisms. By rigorously prioritizing candidate genes and mapping them to specific cell types, we provide a comprehensive genetic map of VC and highlight potentially safe targets for future therapeutic development.