Abstract
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 cis-acting associations due to study limitations. While trans-eQTL 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.
Highlights
Prostate cancer (PRCA) is one of the most heritable cancers, with latest estimates of the genetic contribution to total risk near 58% [1]
Of the 3130 candidate cis-expression quantitative trait loci (eQTL) target genes, we identified 86 significant cis-genes associated with 72 unique PRCA risk loci variants (Supplementary Table 1)
Three cis-mediator trios resulted in mediation p-values below the Bonferroni-adjusted significance threshold of 0.05/1168 ≈ 4.3E-05: rs11263762 →HNF1B→SRC, rs11263762→HNF1B→melanomainhibitory activity 2 (MIA2), and rs10993994→MSMB→N-myc downstream regulated gene 1 (NDRG1)
Summary
Prostate cancer (PRCA) is one of the most heritable cancers, with latest estimates of the genetic contribution to total risk near 58% [1]. A total of 202 PRCA risk-associated loci have been reported by genome-wide association studies [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16], which collectively explain approximately one third of the total familial risk The majority of these variants does not occur within genic regions and are presumed to be regulatory in nature. Multiple expression quantitative trait loci (eQTL) studies have investigated associations between PRCA www.impactjournals.com/oncotarget susceptibility loci and transcript expression levels of nearby genes [17, 18]. These studies have identified a large number of dysregulated genes that may be relevant to the development and progression of PRCA. Other approaches, including adaptive false discovery rate estimation [25] and cross-phenotype meta-analysis [26], have focused on trans-eQTL “hotspots”, whereby genetic loci are associated in trans with expression levels of multiple transcripts
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