• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.

We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin-nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study-by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10(-10)). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 x 10(-13) and P < 2.14 x 10(-6)). Loci on chromosome 10 include MSMB, which encodes beta-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 x 10(-5)), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.