EQTL Mendelian randomization to identify genetic insights and regulatory mechanisms in benign prostatic hyperplasia

Abstract

Aim: This study aims to identify key genes and regulatory mechanisms associated with benign prostatic hyperplasia (BPH) using expression quantitative trait locus (eQTL)-based Mendelian randomization and integrative bioinformatics analyses.

Methods: Cis-expression quantitative trait locus (cis-eQTL) data were obtained from the eQTLGen Consortium. Genome-wide association study (GWAS) summary statistics for BPH were retrieved from the FinnGen biobank and the IEU OpenGWAS database. Gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Mendelian randomization and colocalization analyses were performed to prioritize BPH-associated genes. Subsequent analyses included gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), immune infiltration analysis, transcription factor prediction, miRNA network construction, and metabolic correlation analysis.

Results: A total of 105 and 11 BPH-associated genes were identified in the training and validation datasets, respectively. Colocalization analysis further prioritized five key genes, including C2 (Complement Component 2), GUCY1B2 (Guanylate Cyclase 1 Soluble Subunit Beta 2), OLFM4 (Olfactomedin 4), ITPR1 (Inositol 1,4,5-Trisphosphate Receptor Type 1), and KLHL36 (Kelch Like Family Member 36). Functional analyses indicated that these genes were involved in multiple BPH-related pathways, including tumor protein p53 (p53), mechanistic target of rapamycin (mTOR), transforming growth factor-beta (TGF-β), and interleukin-17 (IL-17) signaling. These genes were also associated with immune cell infiltration, immune-related factors, transcriptional regulation, miRNA interactions, metabolic pathways, and disease-related gene networks.

Conclusion: Five candidate genes associated with BPH were identified, and their potential regulatory mechanisms were characterized through integrative genetic and transcriptomic analyses. These findings provide new insights into the molecular basis of BPH and may inform future biomarker development and mechanism-driven therapeutic strategies, although further experimental validation remains necessary.

Keywords

Benign prostatic hyperplasia / Mendelian randomization / key genes and regulatory networks

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