Abstract
Large-scale genome-wide association studies have identified multiple singlenucleotide 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 cis-acting associations due to study limitations. While transeQTL scans suffer from high testing dimensionality, recent evidence indicates most trans-eQTL associations are mediated by cis-regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis-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 trans-eQTL associations that were significantly mediated by cis-regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B, and target trans-genes with known HNF response elements (MIA2, SRC, SEMA6A, KIF12). We additionally identified evidence of cis-acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1. The majority of these cis-mediator relationships demonstrated trans-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.
Original language | English (US) |
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Pages (from-to) | 85896-85908 |
Number of pages | 13 |
Journal | Oncotarget |
Volume | 8 |
Issue number | 49 |
DOIs | |
State | Published - Oct 17 2017 |
Keywords
- Expression quantitative trait loci
- Genetic risk
- Mediation
- Prostate cancer
ASJC Scopus subject areas
- Oncology