Dissecting shared genetic architecture between pan-cancer and aging-related traits: a genome-wide cross-trait analysis.

Abstract

The association between aging and cancer has been extensively documented in observational studies, but their shared genetic basis remains unclear. Leveraging genome-wide association studies summary statistics of aging and pan-cancer (87,531 cases and 314,193 controls) within the European population, genetic correlation and Mendelian randomization analyses were used to estimate genetic correlations, and infer causal relationships between seven aging-related traits and pan-cancer. We further conducted cross-trait and colocalization analyses to identify shared causal variants and then mapped them to genes. Differential expression analysis, RT-qPCR assays, enrichment analysis, and survival analysis were performed to explore the expression profiles of candidate genes and potential pathways. A significant negative genetic correlation between mvAge and pan-cancer was observed (r_g = -0.158, P = 7.41 × 10^-7). Concurrently, Mendelian randomization results supported a negative impact of pan-cancer on mvAge. We further identified five shared causal variants between mvAge and pan-cancer, and mapped them to five genes (CPA5, IRF4, KLHDC10, TYR, and ZC3HC1). High expression of ZC3HC1 was observed in bladder cancer tissues or bladder cancer cell lines, and was notably associated with low survival probability in bladder cancer. Enrichment analysis between high-ZC3HC1 and low-ZC3HC1 groups highlighted pathways related to chromosome separation and cell cycle. Our findings revealed a shared genetic basis linking aging and pan-cancer. We identified five causal variants in three colocalized loci and mapped them to five shared genes (CPA5, IRF4, KLHDC10, TYR, and ZC3HC1). In an exploratory downstream analysis, we observed that ZC3HC1 was differentially expressed in bladder cancer tissues, and high ZC3HC1 expression was associated with poorer survival outcomes.