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...

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Published in:Oncotarget 2017-10, Vol.8 (49), p.85896-85908
Main Authors: Larson, Nicholas B, McDonnell, Shannon K, Fogarty, Zach, Larson, Melissa C, Cheville, John, Riska, Shaun, Baheti, Saurabh, Weber, Alexandra M, Nair, Asha A, Wang, Liang, O'Brien, Daniel, Davila, Jaime, Schaid, Daniel J, Thibodeau, Stephen N
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Language:English
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Research Paper
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.20717