A transcriptome‐wide association study identifies novel candidate susceptibility genes for prostate cancer risk
Abstract
A large proportion of heritability for prostate cancer risk remains unknown. Transcriptome‐wide association study combined with validation comparing overall levels will help to identify candidate genes potentially playing a role in prostate cancer development. Using data from the Genotype‐Tissue Expression Project, we built genetic models to predict normal prostate tissue gene expression using the statistical framework PrediXcan, a modified version of the unified test for molecular signatures and Joint‐Tissue Imputation. We applied these prediction models to the genetic data of 79 194 prostate cancer cases and 61 112 controls to investigate the associations of genetically determined gene expression with prostate cancer risk. Focusing on associated genes, we compared their expression in prostate tumor vs normal prostate tissue, compared methylation of CpG sites located at these loci in prostate tumor vs normal tissue, and assessed the correlations between the differentiated genes' expression and the methylation of corresponding CpG sites, by analyzing The Cancer Genome Atlas (TCGA) data. We identified 573 genes showing an association with prostate cancer risk at a false discovery rate (FDR) ≤ 0.05, including 451 novel genes and 122 previously reported genes. Of the 573 genes, 152 showed differential expression in prostate tumor vs normal tissue samples. At loci of 57 genes, 151 CpG sites showed differential methylation in prostate tumor vs normal tissue samples. Of these, 20 CpG sites were correlated with expression of 11 corresponding genes. In this TWAS, we identified novel candidate susceptibility genes for prostate cancer risk, providing new insights into prostate cancer genetics and biology.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 25, 2021
- Source ID
- 10.1002/ijc.33808
Entities
People
- Chong Wu
- Christopher A. Haiman
- Dan Zhou
- Duo Liu
- Emily G. Nikas
- Eric R. Gamazon
- Jason B. Nikas
- Jingjing Zhu
- Lang Wu
- Liang Wang
- Nancy J. Cox
- Nicholas Mancuso
- Nikos T. Mitanis
- Stephen J. Freedland
- Yanfa Sun
Organizations
- Canadian Institutes of Health Research
- Cancer Research UK
- Cedars-Sinai Medical Center
- Durham VA Medical Center
- Florida State University
- H. Lee Moffitt Cancer Center & Research Institute
- Harbin Medical University
- Harbin Medical University Cancer Hospital
- Longyan University
- National Institutes of Health
- Swedish Research Council
- United States Department of Defense
- University of Cambridge
- University of Hawaiʻi at Mānoa
- University of Minnesota
- University of Southern California
- University of the Aegean
- Vanderbilt University