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

Nicholas Larson, Shannon K. McDonnell, Zach Fogarty, Melissa C. Larson, John Cheville, Shaun Riska, Saurabh Baheti, Alexandra M. Weber, Asha A. Nair, Liang Wang, Daniel O'Brien, Jaime Davila, Daniel J Schaid, Stephen N Thibodeau

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)85896-85908
Number of pages13
JournalOncotarget
Volume8
Issue number49
DOIs
StatePublished - Oct 17 2017

Fingerprint

Quantitative Trait Loci
Prostate
Prostatic Neoplasms
Transcription Factors
Gene Expression
Genome-Wide Association Study
Response Elements
Genes
Down-Regulation
RNA

Keywords

  • Expression quantitative trait loci
  • Genetic risk
  • Mediation
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 8, No. 49, 17.10.2017, p. 85896-85908.

Research output: Contribution to journalArticle

Larson, N, McDonnell, SK, Fogarty, Z, Larson, MC, Cheville, J, Riska, S, Baheti, S, Weber, AM, Nair, AA, Wang, L, O'Brien, D, Davila, J, Schaid, DJ & Thibodeau, SN 2017, 'Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci', Oncotarget, vol. 8, no. 49, pp. 85896-85908. https://doi.org/10.18632/oncotarget.20717
Larson, Nicholas ; 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. / Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci. In: Oncotarget. 2017 ; Vol. 8, No. 49. pp. 85896-85908.
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