title: Polymorphisms influencing prostate-specific antigen concentration may bias genome-wide association studies on prostate cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  The influence of SNPs on PSA concentration should be considered when interpreting results from GWAS on prostate cancer.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dluzniewski
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. eplatz@jhsph.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
mesh_terms: D000368:Aged; D015331:Cohort Studies; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics*
chemical_list: D017430:Prostate-Specific Antigen