Integrative genomic profiling identifies MLPH as a candidate gene in prostate cancer

Abstract Background: Prostate cancer (PCa) is a highly heterogeneous malignancy with complex genetic underpinnings. While genome-wide association studies (GWAS) have identified numerous genetic loci linked to PCa susceptibility, integrative multi-omics validation is still needed to confirm causality and uncover functional roles of candidate genes in PCa pathogenesis. Objectives: This study aims to systematically identify and prioritize candidate genes associated with PCa risk through integrative multi-omics analyses, and to elucidate their potential biological roles in tumorigenesis. Materials and Methods: We applied cross-tissue and single-tissue transcriptome-wide association studies (TWAS) on the largest available GWAS and the Genotype-Tissue Expression (GTEx) V8 datasets. Subsequent gene-level association tests refined candidate signals. Summary data-based Mendelian randomization (SMR) and Bayesian colocalization were conducted to infer causality. Expression validation was performed at both transcriptional and protein levels. Gene network and pathway enrichment analyses further explored functional contexts. Results: A total of 1,248 genes were identified by single-tissue TWAS, with 35 robust genes confirmed after conditional analysis overlapping with cross-tissue results. Integration with gene-level association test yielded 23 consensus candidate genes. SMR and colocalization prioritized MLPH and GGCX as putative causal genes. MLPH was significantly upregulated in PCa tissues at both the mRNA and protein levels, while GGCX showed no difference. Functional analyses revealed the involvement of MLPH in vesicle-mediated transport and androgen-related signaling pathways, highlighting its biological relevance in PCa pathogenesis. Discussion and Conclusion: Our integrative multi-omics approach establishes MLPH as a biologically and statistically supported gene linked to PCa susceptibility. Its roles in vesicle trafficking and hormone-regulated pathways underscore its potential as a therapeutic target, warranting further mechanistic and translational investigations.