PROJECT SUMMARY/ABSTRACT Although genome-wide association studies (GWAS) have been extremely successful in identifying numerous germline variants associated to risk for prostate cancer, the causal mechanism between genetic variation and disease risk remains largely unknown at the vast majority of these loci. This prohibits the full realization of novel drug targets and/or personalized treatments. In the quest to address this gap, post-GWAS studies are experiencing a “big data” revolution driven by the exponentially decreasing costs of high-throughput genomic assays. Multiple layers of data (genetic variation, transcriptome levels, epigenetic modifications, localization of tissue-specific regulatory sites, 3D interactions, etc.) are routinely collected in increasingly large cohorts of individuals. This raises the need for rigorous computational and experimental frameworks that integrate various types of data to identify and validate causal genes and variants in prostate cancer. Here we propose a rigorous framework aimed at loci where risk is mediated through alteration in gene expression levels. We deliberately and exhaustively propose to examine all risk loci for prostate cancer to prioritize causal variants and genes and to functionally validate them in prostate cancer tissue and cell lines.

PROJECT NARRATIVE Genetic studies of prostate cancer have been tremendously successful in identifying more than 150 genomic risk regions that harbor variants increasing risk. Unfortunately, the causal mechanisms through which disease risk is altered at these loci remains elusive. In this proposal we develop and apply new statistical and experimental methods to find causal variants and genes for prostate cancer. Our proposal centers on germline variation that alter disease risk through up/down regulation of key risk genes.