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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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689655/
https://www.ncbi.nlm.nih.gov/pubmed/29156765
http://dx.doi.org/10.18632/oncotarget.20717
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author 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.
author_facet 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.
author_sort Larson, Nicholas B.
collection PubMed
description 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.
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spelling pubmed-56896552017-11-17 Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci 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. Oncotarget Research Paper 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. Impact Journals LLC 2017-09-08 /pmc/articles/PMC5689655/ /pubmed/29156765 http://dx.doi.org/10.18632/oncotarget.20717 Text en Copyright: © 2017 Larson et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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.
Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title_full Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title_fullStr Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title_full_unstemmed Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title_short Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
title_sort network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689655/
https://www.ncbi.nlm.nih.gov/pubmed/29156765
http://dx.doi.org/10.18632/oncotarget.20717
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