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Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Mancuso, N; Gayther, S; Gusev, A; Zheng, W; Penney, KL; Kote-Jarai, Z; Eeles, R; ... The PRACTICAL consortium, PC; + view all (2018) Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nature Communications , 9 , Article 4079. 10.1038/s41467-018-06302-1. Green open access

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Abstract

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

Type: Article
Title: Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-018-06302-1
Publisher version: http://doi.org/10.1038/s41467-018-06302-1
Language: English
Additional information: © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Cancer genetics, Gene expression, Genome-wide association studies
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Applied Health Research
URI: https://discovery.ucl.ac.uk/id/eprint/10061217
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