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Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development.

Original publication

DOI

10.1038/ng.3523

Type

Journal article

Journal

Nat Genet

Publication Date

04/2016

Volume

48

Pages

387 - 397

Keywords

Base Sequence, Binding Sites, CCCTC-Binding Factor, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Protein Binding, Quantitative Trait Loci, Repressor Proteins, Risk Factors, Sequence Analysis, DNA