Abstract
While genome-wide association studies (GWAS) have revealed thousands of disease risk single nucleotide polymorphisms (SNPs), their functions remain largely unknown. Recent studies have suggested the regulatory roles of GWAS risk variants in several common diseases; however, the complex regulatory structure in prostate cancer is unclear. We investigated the potential regulatory roles of risk variants in two prostate cancer GWAS datasets by their interactions with expression quantitative trait loci (eQTL) and/or transcription factor binding sites (TFBSs) in three populations. Our results indicated that the moderately associated GWAS SNPs were significantly enriched with cis-eQTLs and TFBSs in Caucasians (CEU), but not in African Americans (AA) or Japanese (JPT); this was also observed in an independent pan-cancer related SNPs from the GWAS Catalog. We found that the eQTL enrichment in the CEU population was tissue-specific to eQTLs from CEU lymphoblastoid cell lines. Importantly, we pinpointed two SNPs, rs2861405 and rs4766642, by overlapping results from cis-eQTL and TFBS as applied to the CEU data. These results suggested that prostate cancer associated SNPs and pan-cancer associated SNPs are likely to play regulatory roles in CEU. However, the negative enrichment results in AA or JPT and the potential mechanisms remain to be elucidated in additional samples.
Highlights
Prostate cancer (PrCa) is the most prevalent noncutaneous cancer diagnosed in men in the United States, with about one in six men developing PrCa during their lifetime [1]
We attempted to study the regulatory roles for two types of association data: moderately significant single nucleotide polymorphisms (SNPs) that were associated with PrCa and cancer-associated SNPs from the genome-wide association studies (GWAS) Catalog that reached the genome-wide significance level
This is the first investigation of the enrichment of associated SNPs with expression quantitative trait loci (eQTL) and transcription factor binding sites (TFBSs) in prostate cancer in different populations
Summary
Prostate cancer (PrCa) is the most prevalent noncutaneous cancer diagnosed in men in the United States, with about one in six men developing PrCa during their lifetime [1]. Great efforts have been made during the past several decades to elucidate the underlying etiology of this disease. Among these efforts, genome-wide association studies (GWAS) have been one of the most valuable approaches to discover potential genetic susceptibilities. As of December 4, 2012, a total of 22 PrCa GWA studies have been deposited into the GWAS Catalog at the National Human Genome Research Institute (NHGRI) [4], yielding more than 100 common single nucleotide polymorphisms (SNPs) that potentially contribute to PrCa risk. The reported SNPs could www.impactjournals.com/oncotarget only explain a small proportion of the genetic variances that might contribute to this disease and most significantly associated SNPs are located in non-coding regions with unknown functional annotations [4]. The original GWA studies typically reported only a few SNPs that reach the strigent genome-wide significance (i.e., p < 5×10-8), while neglecting those SNPs with moderate or weak significance (5×10-8 < p < 0.05)
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