Contribution of leukocyte telomere length to cardiovascular disease onset from genome-wide cross-trait analysis

Telomere shortening is a well-established marker of cellular aging and genomic instability. While the relationship between leukocyte telomere length and cardiovascular diseases has long been of interest, their genetic interplay remains incompletely understood. In this study, we observe substantial genetic overlap beyond genome-wide correlations and identify a potential causal relationship between leukocyte telomere length and coronary artery disease. Specifically, we discover 248 pleiotropic loci, 22 of which show strong evidence of colocalization. Some shared loci implicate multiple pleiotropic genes across different trait pairs, including ALDH2, ACAD10, TMEM116, SH2B3 (all at 12q24.12), TMED6 (16q22.1), SERPINF1 (17p13.3), and XPO7 (8p21.3). Functional analysis highlights key pathways involved in DNA biosynthesis and telomere maintenance. Notably, SH2B3 is validated through proteome-wide Mendelian randomization analysis, suggesting its potential as a therapeutic target. Here we report the shared genetic basis between leukocyte telomere length and cardiovascular diseases, providing valuable insights into future therapeutic developments.