Dense Genome-Wide SNP Linkage Scan in 301 Hereditary Prostate Cancer Families Identifies Multiple Regions with Suggestive Evidence for Linkage

The search for susceptibility loci in hereditary prostate cancer (HPC) has proven challenging due to genetic and disease heterogeneity. Multiple risk loci have been identified to date, however few loci have been replicated across independent linkage studies. In addition, most previous analyses have been hampered by the relatively poor information content provided by microsatellite scans. To overcome these issues, we have performed linkage analyses on members of 301 HPC families genotyped using the Illumina SNP linkage panel IVb. The information content for this panel, averaged over all pedigrees and all chromosomes, was 86% (range 83–87% over chromosomes). Analyses were also stratified on families according to disease aggressiveness, age at diagnosis and number of affected individuals to achieve more genetically homogeneous subsets. Suggestive evidence for linkage was identified at 7q21 (HLOD = 1.87), 8q22 (KCLOD = 1.88) and 15q13–q14 (HLOD = 1.99) in 289 Caucasian families, and nominal evidence for linkage was identified at 2q24 (LOD = 1.73) in 12 African American families. Analysis of more aggressive prostate cancer phenotypes provided evidence for linkage to 11q25 (KCLOD = 2.02), 15q26 (HLOD = 1.99) and 17p12 (HLOD = 2.13). Subset analyses according to age at diagnosis and number of affected individuals also identified several regions with suggestive evidence for linkage, including a KCLOD of 2.82 at 15q13–q14 in 128 Caucasian families with younger ages at diagnosis. The results presented here provide further evidence for a prostate cancer susceptibility locus on chromosome 15q and demonstrate the power of utilizing high information content SNP scans in combination with homogenous collections of large prostate cancer pedigrees.