Abstract 1301: Identification of novel susceptibility loci and genes for prostate cancer risk: A large transcriptome-wide association study in over 143,000 subjects

Abstract

Abstract Common genetic variants in over 150 loci have been found to be associated with prostate cancer (PrCa) risk through GWAS. These variants, however, explain only a small fraction of PrCa heritability, and the genes responsible for the detected associations remain largely unknown. It has been suggested that many GWAS-identified associations may be driven by the regulation of risk variants on the expression of disease causal genes. To identify novel PrCa risk loci and possible causal genes at known risk loci, we performed a transcriptome-wide association study (TWAS) to evaluate associations of genetically predicted gene expressions with PrCa risk. We used RNA sequencing data from normal prostate tissues and high-density genotyping from 73 European descendants included in the Genotype-Tissue Expression Project and established genetic models to predict gene expression level. Given that the regulatory mechanisms for most genes are similar across most human tissues, we also built cross-tissue models using gene expression data generated in all tissues from 369 European descendants to increase the statistical power. Based on prediction performance, we selected 22,126 genes and conducted association analyses of their predicted expression with PrCa risk using GWAS data obtained from more than 143,000 subjects included in PRACTICAL/ELLIPSE consortia. We identified 140 genes showing an association of their predicted expression levels with PrCa risk at P < 2.26×10-6, a Bonferroni-corrected significance threshold, including 105 protein-coding genes, 33 long non-coding RNAs, and 2 processed transcripts. Seven of these associated genes are located more than 1Mb away from any of the risk variants identified in PrCa GWAS, representing potential novel risk loci. Of the remaining 133 genes located in known risk loci, 100 have not been reported from previous eQTL analyses. The associations for 25 of these genes remained significant at P < 3.76×10-4 (0.05/133) after adjusting for the risk variants reported in the initial GWAS. Our study also identified 33 genes that were previously reported based on eQTL and fine-mapping analyses. For many of the identified genes, somatic changes of indels, nonsense mutations, splice site variants, translation start site variants, or missense mutations were detected in PrCa patients in the TCGA, including known PrCa driver genes NKX3-1 and PLXNA1. Pathway enrichment analysis showed that cancer related functions were significantly enriched for the identified genes. The top canonical pathways identified included prostate cancer signaling, ATM signaling, AMPK signaling, protein ubiquitination pathway, and antigen presentation pathway. In summary, we conducted the first large PrCa TWAS and identified multiple novel susceptibility loci and genes for PrCa risk. Our study provided substantial new information towards the understanding of PrCa genetics and biology. Citation Format: Lang Wu, Jirong Long, Yingchang Lu, Xingyi Guo, Bogdan Pasaniuc, Kathryn L. Penney, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles, Wei Zheng, the PRACTICAL consortium. Identification of novel susceptibility loci and genes for prostate cancer risk: A large transcriptome-wide association study in over 143,000 subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1301. doi:10.1158/1538-7445.AM2017-1301