Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively
large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three
distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded
features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined
67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946),
African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry.
Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10−4
–5.6 × 10−3
) and in 30 regions
5604 | Human Molecular Genetics, 2015, Vol. 24, No. 19
we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic
sample. Novel secondary signals (P < 5.0 × 10−6
) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12).
Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants
(29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were
detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated
variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20
(36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results
have prioritized subsets of candidate variants for downstream functional evaluation.