Polymorphisms influencing prostate-specific antigen concentration may bias genome-wide association studies on prostate cancer.

Abstract

Genome-wide association studies (GWAS) have produced weak (OR = 1.1-1.5) but significant associations between single nucleotide polymorphisms (SNPs) and prostate cancer. However, these associations may be explained by detection bias caused by SNPs influencing PSA concentration. Thus, in a simulation study, we quantified the extent of bias in the association between a SNP and prostate cancer when the SNP influences PSA concentration. We generated 2,000 replicate cohorts of 20,000 men using real-world estimates of prostate cancer risk, prevalence of carrying ≥1 minor allele, PSA concentration, and the influence of a SNP on PSA concentration. We modeled risk ratios (RR) of 1.00, 1.25, and 1.50 for the association between carrying ≥1 minor allele and prostate cancer. We calculated mean betas from the replicate cohorts and quantified bias under each scenario. Assuming no association between a SNP and prostate cancer, the estimated mean bias in betas ranged from 0.02 to 0.10 for ln PSA being 0.05 to 0.20 ng/mL higher in minor allele carriers; the mean biased RRs ranged from 1.03 to 1.11. Assuming true RRs = 1.25 and 1.50, the biased RRs were as large as 1.39 and 1.67, respectively. Estimates of the association between SNPs and prostate cancer can be biased to the magnitude observed in published GWAS, possibly resulting in type I error. However, large associations (RR > 1.10) may not fully be explained by this bias. The influence of SNPs on PSA concentration should be considered when interpreting results from GWAS on prostate cancer.