Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Abstract

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10^-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

Fig. 1

LocusExplorer plots of the 12 variants at 8q24 significantly associated with PCa risk. ‘Marginal’ and ‘Conditional’ Manhattan plot panels show marginal and conditional association results, respectively. Variant positions (x-axis) and −log₁₀ p-values from the Wald test (y-axis) are shown, with the red line indicating the threshold for genome-wide significant association with PCa risk (p ≤ 5 × 10⁻⁸) and blue peaks local estimates of recombination rates. The position of the 12 independent variants is labeled in each plot. Clusters of correlated variants for each independent signal are distinguished using different colors and also depicted on the ‘LD r² Hits’ track. Stronger shading indicates greater correlation with the lead variant, with variants not correlated at r² ≥ 0.2 with any lead variant uncolored. Pairwise correlations are based on the European ancestry (EUR) panel from the 1000 Genomes Project (1KGP) Phase 3. The relative position of RefSeq genes and biological annotations are shown in the ‘Genes’ and ‘Biofeatures’ panels, respectively. Genes on the positive strand are denoted in green and those on the negative strand in purple. Annotations displayed are: histone modifications in ENCODE tier 1 cell lines (Histone track), the positions of any variants that were eQTLs with prostate tumor expression in TCGA prostate adenocarcinoma samples and the respective genes for which expression is altered (eQTL track), chromatin state categorizations in the PrEC cell-line by ChromHMM (ChromHMM track), the position of conserved element peaks (Conserved track) and the position of DNaseI hypersensitivity site peaks in ENCODE prostate cell-lines (DNaseI track). The data displayed in this plot may be explored interactively through the LocusExplorer application (http://www.oncogenetics.icr.ac.uk/8q24/)