Discovery Expansion and Replication

全基因组关联研究提供了一种强大的方法来识别与之相关的常见遗传变异 有疾病风险。已有20多个基因位点与前列腺癌有关，但这些基因座解释的前列腺癌家族聚集性不到四分之一，这表明仍有许多进一步的基因座有待发现。在这个项目中，我们计划结合来自8个GWAS的数据，包括超过14,000个病例和19,000个欧洲人、非裔美国人、日本人和拉美人血统的对照。这一联合分析将被用于在第二阶段选择3000个SNPs进行进一步的基因分型，涉及10,000个欧洲血统的病例和10,000个对照，以及4,000个非裔美国人祖先的3,000个SNPs和4,000个非裔美国人祖先的对照。 在这一阶段确定的相关性将在45,000例前列腺癌病例和53,000例对照中得到特征。除了与前列腺癌有关外，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。对于已确定的易感基因座，我们将尝试定义可能的致病变异，利用1000基因组计划数据中的变异目录，以及14,000例病例和14,000名欧洲和非裔美国人祖先的密集基因分型。该项目中所描述的基因位点很可能为该疾病的潜在生物学提供新的洞察力(将在配套项目2中进行)。此外，易感变异的特征， 与其他风险因素相结合，将提高确定前列腺癌个人风险概况的能力，从而为疾病预防和管理战略提供参考(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).