Elucidating Cellular Senescence-related Genes in Benign Prostatic Hyperplasia Through Mendelian Randomization and Single-cell RNA Sequencing

BACKGROUND: Benign prostatic hyperplasia (BPH) is a widely observed disorder in older men, with substantial evidence indicating that cellular senescence serves a pivotal function in its progression. This investigation seeks to pinpoint cellular senescence-related genes causally connected with BPH and to examine their expression and regulatory networks across distinct prostate cells. METHODS: Using exposure data from the eQTLGen database and outcome data from both FinnGen Consortium and UKB database, Mendelian randomization was utilized to determine cell senescence genes that are causally linked to BPH. These associations were further validated through colocalization analysis. Expression patterns of these genes in different prostate cells were assessed via single-cell RNA sequencing, and changes along pseudotime were tracked. Regulatory networks were evaluated using single-cell regulatory network inference and clustering to identify key transcription factors involved. RESULTS: Six cell senescence genes causally linked to BPH were identified through Mendelian randomization. ATM, ATRAID, MAP2K1, and TP53 were identified as protective factors, whereas ITPR1 and SENP7 were associated with increased risk. Colocalization analysis suggested that ATM and TP53 are likely to share the same variant implicated in BPH. MAP2K1 expression demonstrated a steady decline along inferred pseudotime across fibroblasts, macrophages, T cells, and epithelial cells, while the remaining 5 genes exhibited an opposite trend. ATF3, EGR1, and FOS were pinpointed as the core transcription factors regulating these genes. CONCLUSIONS: These observations emphasize consistent expression patterns among different prostate cell types and suggest a highly interconnected regulatory network that underpins BPH pathology, thereby providing fresh perspectives on the molecular mechanisms underlying the disease.