Discovery Expansion and Replication

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Genome-wide association studies provide a powerful approach to identify common genetic variants associated with disease risk. More than twenty genetic loci have been associated with prostate cancer, but these explain less than one quarter of the familial aggregation of the disease, indicating that many further loci remain to be found. In this project, we plan to combine data from 8 GWAS, including more than 14,000 cases and 19,000 controls of European, African-American, Japanese and Latino ancestry. This combined analysis will be used to select 3,000 SNPs for further genotyping in a second stage, involving 10,000 cases and 10,000 controls of European ancestry, and further 3,000 SNPs in 4,000 cases and 4,000 controls of African-American ancestry. Associations identified at this stage will then be characterised in >45,000 prostate cancer cases and 53,000 controls. In addition to associations with prostate cancer, we will look specifically for loci associated with eariy onset disease, and with aggressive disease. For susceptibility loci that are identified, we will attempt to define the likely causative variants, utilising the catalog of variants from the 1000 Genome Project data, together with dense genotyping in 14,000 cases and 14,000 controls for European and African-American ancestry. Genetic loci that are characterised in this project are likely to provide new insights into the underiying biology of the disease (to be pursued in the companion Project 2). In addition, the characterisation of susceptibility variants, in combination with other risk factors, will improve the ability to define individual risk profiles for prostate cancer, and hence inform strategies for disease prevention and management (to be pursued in Project 3).