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

Nicholas Mancuso, Simon Gayther, Alexander Gusev, Wei Zheng, Kathryn L. Penney, Zsofia Kote-Jarai, Rosalind Eeles, Matthew Freedman, Christopher Haiman, Bogdan Pasaniuc
doi: https://doi.org/10.1101/345736
Nicholas Mancuso
1Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
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Simon Gayther
2The Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Alexander Gusev
3Dana Farber Cancer Institute, Boston, MA
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Wei Zheng
4Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
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Kathryn L. Penney
5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
6Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts
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Zsofia Kote-Jarai
7Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK
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Rosalind Eeles
7Division of Genetics and Epidemiology, The Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK
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Matthew Freedman
8Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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Christopher Haiman
9Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Bogdan Pasaniuc
1Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
10Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA
11Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA
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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=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 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 pre-defined level; this reduced the list of 235 associations to 120 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.

Footnotes

  • ↵* Members from the PRACTICAL Consortium, CRUK, BPC3, CAPS and PEGASUS are provided in the supplementary note.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 14, 2018.
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Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Nicholas Mancuso, Simon Gayther, Alexander Gusev, Wei Zheng, Kathryn L. Penney, Zsofia Kote-Jarai, Rosalind Eeles, Matthew Freedman, Christopher Haiman, Bogdan Pasaniuc
bioRxiv 345736; doi: https://doi.org/10.1101/345736
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Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Nicholas Mancuso, Simon Gayther, Alexander Gusev, Wei Zheng, Kathryn L. Penney, Zsofia Kote-Jarai, Rosalind Eeles, Matthew Freedman, Christopher Haiman, Bogdan Pasaniuc
bioRxiv 345736; doi: https://doi.org/10.1101/345736

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