Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci.

Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to -acting associations due to study limitations. While -eQTL scans suffer from high testing dimensionality, recent evidence indicates most -eQTL associations are mediated by -regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive -mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple -eQTL associations that were significantly mediated by -regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor , and target -genes with known HNF response elements (, , , ). We additionally identified evidence of -acting down-regulation of via rs10993994 corresponding to reduced co-expression of . The majority of these -mediator relationships demonstrated -eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer.