Abstract
BACKGROUND: While epidemiological studies suggest an association between leukocyte telomere length (LTL) and renal cell carcinoma (RCC), the genetic basis underlying this relationship remains to be elucidated. METHODS: We analyzed genome-wide association studies (GWAS) summary statistics from LTL (n = 472,174) and RCC(3,926 cases; 378,749 controls) cohorts. Comprehensive cross-trait analyses examined genetic correlations, causality, tissue enrichment, and pleiotropic loci. RESULTS: We identified significant genetic correlation between LTL and RCC (correlation = 0.0379, p = 0.0012) at both genome-wide and local levels. Meta-analysis revealed 25 novel pleiotropic loci, including a co-localized variant (rs1874330). Novel tissue-specific enrichment was observed in uterine and testicular tissues, with shared functional genes affecting both traits. Mendelian randomization provided evidence for a causal effect of LTL on RCC risk. CONCLUSION: This study establishes genetic links between LTL and RCC through shared architecture, tissue-specific patterns, and causal pathways, suggesting potential therapeutic targets and risk markers for future validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-025-03565-1.