Familial clustering of early-onset prostate cancer best fits a model of autosomal dominant inheritance of a rare, high-risk allele, predisposing 9% of all prostate cancer occurrence. Prostate cancer is inherited in a Mendelian fashion in these families, providing an opportunity to apply linkage analysis to this complex disease. We have developed and applied high-throughput fluorescent methods to enable genotyping of 500 individuals from affected U.S. families at a 10 centiMorgan density. Allele identification is accomplished in a semi-automated fashion. The genome survey has been completed with an estimated error rate of 0.26% and failure rate of 2%. We are now completing a higher resolution map of at least 5cM in regions not excluded by the survey. Both parametic and nonparametric methods of analysis are being employed. Supplemental U.S. pedigrees are now also being genotyped in the higher density survey to increase power to identify linkage. We are also collecting extended pedigrees with prostate cancer in Finland and Sweden as confirmatory populations.
