Genetic variants in WDR4 influencing m7G modification are associated with prostate cancer susceptibility

Introduction The associations between genetic variants in N7-methylguanosine (m7G)-related genes and prostate cancer susceptibility remain unclear. This study investigated the relationship between WDR4 genetic variants and prostate cancer risk and explored their potential regulatory relevance. Methods A discovery cohort from the PLCO study and an independent validation cohort from the PRACTICAL consortium were analyzed using logistic regression models. Functional annotation, expression quantitative trait locus analysis, RNA secondary-structure prediction, gene-expression analysis, survival analysis, and single-cell transcriptomic analysis were performed to investigate the potential biological relevance of associated variants. Results The rs8130270 variant in WDR4 was associated with prostate cancer susceptibility in the discovery cohort (OR = 0.89, 95% CI = 0.82–0.96, P(FDR) = 2.65 × 10–2) and was validated in the PRACTICAL cohort (OR = 0.98, 95% CI = 0.97–1.00, P = 4.16 × 10–2). The rs8130270 C allele was associated with lower WDR4 expression in prostate tissue. WDR4 expression was higher in prostate cancer tissues, and high WDR4 expression was associated with poorer overall survival (HR = 1.67, 95% CI = 1.06–2.64, P = 2.00 × 10–2). Single-cell analysis showed that WDR4 was expressed across multiple immune and tumor-associated cell populations. Discussion These findings suggest that rs8130270 in WDR4 may contribute to prostate cancer susceptibility through effects on WDR4 expression and provide genetic evidence supporting a potential role of WDR4-related m7G regulation in prostate cancer.