Contribution of leukocyte telomere length to major cardiovascular diseases onset: phenotypic and genetic insights from a large-scale genome-wide cross-trait analysis

Telomere shortening, a marker of cellular aging and genomic instability, has been epidemiologically linked to an increased risk of various cardiovascular diseases (CVDs). However, shared genetic determinants involved in these associations remain unclear. We composed an atlas of the shared genetic associations between leukocyte telomere length (LTL) and six major CVDs by investigating shared genetic elements, encompassing SNPs, genes, biological pathways, and protein targets with pleiotropic implications. Extensive genetic overlaps beyond genetic correlations were observed, but no causal relationships were established. We identified 248 independent pleiotropic genomic risk loci, implicating 50 unique genes in two or more trait pairs, especially the SH2B3 gene, which was further validated by a proteome-wide Mendelian Randomization study. Functional analysis demonstrated a link to both DNA biosynthetic processes and telomere maintenance mechanisms. These findings suggest a genetic link between LTL and CVDs, highlighting a shared genetic basis crucial for developing future interventions and therapeutic targets.