Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Abstract

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10^-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment.

Figure 1. Flow chart highlighting the approach and samples used to detect SNPs associated with PSA from GWAS.

First we undertook an unconditional discovery GWAS in the KP non-Hispanic white non-cases. Thirty-eight SNPs associated with PSA (P<5 × 10⁻⁷) were then included as covariates in a second conditional discovery GWAS. All SNPs associated with PSA (P<5 × 10⁻⁷) from these two GWAS (38+23) were evaluated for replication in two steps, first in an analysis of the replication cohorts alone, and then in a meta-analysis combining the discovery and replication cohorts. A total of 40 independent SNPs (27 in unconditional GWAS, 13 in conditional GWAS) met criteria of combined meta P<5 × 10⁻⁸, replication meta P<0.1, and same effect direction in discovery/replication.

Figure 2. Results from a GWAS of PSA levels in 28,503 Kaiser Permanente non-Hispanic white non-cases.

P values are for variant associations with log-transformed PSA levels, adjusted for age and ancestry principal components using a linear regression model. Black and grey peaks indicate novel findings. Dark purple and magenta indicates previously reported PSA level associated genotyped and imputed hits, respectively, and light purple and magenta indicate those within 0.5 Mb of previously reported hits that were replicated at genome-wide significance. Dark pink and red points denote previously reported PCa SNPs genotyped and imputed, respectively, and pink and orange indicate those within 0.5 Mb of previously reported PCa SNPs genotyped and imputed. Dark blue and green points denote the previously reported genotyped and imputed, respectively, SNPs associated with PSA levels only (and not PCa), and light blue and green those within 0.5 Mb previously reported hits. Circles denoted genotyped SNPs and triangles represent imputed SNPs.

Figure 3. Comparison of the effect of SNPs on PSA levels versus on prostate cancer (PCa) in KP non-Hispanic whites.

Results are from separate models regressing PSA level (linear regression) or PCa (logistic regression, unadjusted for PSA levels are small circles, adjusted for PSA levels are large circles) on each of the 40 PSA level SNPs from Tables 2 and 3 and the 105 previously identified PCa SNPs. (a) Effect sizes. (b) P values. Red points are associated with PSA levels only (from Tables 2 and 3), blue with PCa only (P<0.00125, a Bonferroni correction for 40 SNPs), purple with both PSA and PCa (for small circles, this also includes previously identified PCa associated SNPs), and black are previously identified PCa associated SNPs (not significant here). Previously reported PCa SNPs within 0.5Mb of a PSA SNP were removed: rs1775148, rs6763931, rs2242652, rs10486567, rs2928679, rs1512268, rs12543663, rs10086908, rs1016343, rs13252298, rs6983561, rs116041037, rs445114, rs16902104, rs6983267, rs7000448, rs11986220, rs10993994, rs2252004, rs11568818, 12:114685571, rs11649743, rs7501939 and rs2735839.