Discovery Expansion and Replication

全基因组关联研究提供了一种强有力的方法来识别相关的常见遗传变异 疾病风险。超过20个基因位点与前列腺癌相关，但这些基因位点解释了不到四分之一的家族聚集性疾病，这表明许多进一步的基因位点仍有待发现。在这个项目中，我们计划结合联合收割机数据从8个GWAS，包括超过14,000例和19,000控制欧洲，非洲裔美国人，日本人和拉丁美洲血统。该组合分析将用于在第二阶段中选择3，000个SNP用于进一步基因分型，涉及10，000例欧洲血统病例和10，000例对照，以及4，000例非裔美国人血统病例和4，000例对照中的3，000个SNP。 在此阶段确定的相关性将在> 45，000例前列腺癌病例和53，000例对照中进行表征。除了与前列腺癌的相关性外，我们还将专门寻找与早发性疾病和侵袭性疾病相关的基因座。对于确定的易感基因座，我们将尝试定义可能的致病变异，利用1000个基因组计划数据的变异目录，以及欧洲和非洲裔美国人血统的14，000例病例和14，000例对照的密集基因分型。该项目中表征的遗传位点可能为疾病的基础生物学提供新的见解（将在同伴项目2中进行）。此外，易感性变体的表征， 结合其他风险因素，将提高界定前列腺癌个体风险特征的能力，从而为疾病预防和管理提供信息（将在项目3中进行）。

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).