A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences

Abstract

A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).

Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

Figure 1

Results from a genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente population (8,399 cases and 38,745 controls), highlighting key chromosomal regions. P-values are for variant associations with prostate cancer from trans-ethnic fixed-effects meta-analysis of four race/ethnicity GWAS (non-Hispanic white, Latino, African-American, East Asian), each adjusted for age and ancestry principal components. Horizontal dashed lines indicated genome-wide statistical significance (p<5×10⁻⁸), Bonferroni-corrected significance for 105 know prostate cancer risk variants (p<0.05/105), and nominal significance (p<0.05). Red points denote our findings for the 105 known risk SNPs, and pink indicate results for SNPs within a 0.5Mb window around these SNPs. The new 6q25.3 indel rs4646284 is colored magenta, and the 19q13.33 prostate cancer or PSA SNP rs2659124 is noted in green. Those loci containing previously-reported variants that we replicated at genome-wide significance are noted in black text. Loci with variants that were novel in in the KP GWAS but failed to replicate are noted in gray text.

Figure 2

Regional fixed-effects meta-analysis plots from GWAS in Kaiser Permanente population of the two risk variants that replicated: (a) 6q25.3 (rs4646284), (b) 19q13.33 (rs2659124). The color code for the points represents the r² of each SNP with the risk variant (ranges defined in the legend). The dotted vertical lines pass through the risk variants and the other significant SNPs in the region, on which analyses were conditioned.

Figure 3

Comparison of variant associations from previous reports and results from the KP GWAS meta-analysis for 105 known prostate cancer risk SNPs. Plotted values are the log odds ratios from the previous and current studies. Error lines denote the 95% CIs for the respective studies, colored by chromosome. Blue line is the diagonal and red is regression fit through the points, showing extremely high correlation between the previous and new odds ratios. The SNP rs116041037 appears to be an African-American specific SNP and is an outlier so we left it off of the plot to more easily view the other points; the SNP had a previous OR=2.45 (95% CI=1.65–3.62), and KP OR=2.67 (1.96, 3.64).

Figure 4

Impact of increasing deciles of risk profile scores based on 105 known risk SNPs across different race/ethnicity groups. Risk scores generated by combining the 105 SNPs into a single score, applying the logs odds ratio estimated by previous studies to our KP study population genotype data. Odds ratios for effect of risk profile scores on prostate cancers calculated within each decile of the scores, using the lowest decile of risk profile scores as the referent category. The non-Hispanic white and Latino groups had substantially higher ORs than the African-Americans, and the East Asians always had the lowest ORs.