Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at =60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 x 10(-8) to P = 8.7 x 10(-29)). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10 −8 to P=2.7×10 −33 ).Genome-wide association studies (GWAS) provide a powerful approach to identify common disease alleles. We previously conducted a GWAS 1 , based on genotyping of 541, 129 SNPs in 1,854 clinically detected PrCa cases and 1,894 controls (see Figure 1, stage 1). Follow-up genotyping of SNPs exhibiting strong evidence of association (P<10 −6 ), in a further 3,268 cases and 3,366 controls, allowed us to identify SNPs at 7 susceptibility loci associated with the disease at genome-wide levels of significance 1 . Other studies have identified an additional 8 loci [2][3][4][5][6][7][8][9] . These loci, however, explain only a small fraction of the familial risk of PrCa. Moreover, the strength of the associations that have been detected are generally small (perallele odds ratios, OR, 1.1-1.2), and the power of the existing studies to detect many of the susceptibility alleles has been limited. It is highly likely, therefore, that other PrCa predisposition loci exist, and that such loci should be detectable by studies with larger sample sizes.In an attempt to identify further susceptibility loci, we conducted a more extensive follow-up of SNPs showing evidence of association in stage 1 of our GWAS. We designed a panel of 47,120 SNPs, aiming to include all SNPs with a significant association in stage 1 at P-trend (1df)<.05 or P(2df)<.01 (see Online Methods). These SNPs were genotyped using the Illumina iSELECT platform in 3,894 PrCa cases and 4,055 controls from the United Kingdom (UK) and Australia ( Figure 1, stage 2). After quality control (QC) exclusions (as described in Online Methods), we utilised data from 43,671 SNPs in 3,650 PrCa cases and 3,940 controls. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGenotype frequencies in cases and controls were compared using a 1 degree of freedom (df) Cochran-Armitage trend test (for QQ plots see Supplementary Figure 1). There was little evidence of inflation in the test statistics in the UK samples (estimated inflation factor λ=1.08), but there was more marked inflation in those from Australia (λ=1.23; λ=1.19 for stage 2 overall), suggestive of some population substructure. The Australian samples were selected from three studies (MCCS, RFPCS and EOPCS; see Supplementary Note for cohort descriptions), and further analysis revealed that ...
Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.
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