Building on GWAS for NHLBI-disease: the CHARGE consortium

描述（由申请人提供）： 这项研究提案名为“建立在GWAS基础上的NHLBI疾病：美国CHARGE联盟”，将利用现有的人口，实验室和计算资源来识别易感基因，这些基因是全基因组范围内重要的和重复性良好的GWAS发现心脏，肺和血液疾病及其风险因素。美国CHARGE联盟由多项大型基于人群的纵向队列研究组成，包括社区动脉粥样硬化风险（ARIC）研究N= 15，792，心血管健康研究（CHS）N= 5，888和心脏病研究（FHS）N= 14，428。此外，年轻人冠状动脉风险发展（CARDIA N= 3，756）研究也加入了这一合作努力。对于这些队列中的每一个，DNA样本已经被分离，并且表型数据很容易用于分析。这项研究将采取双管齐下的方法来跟踪GWAS：首先，我们将在影响15种表型的60个基因组区域中进行靶向测序和复制基因分型。对于每种表型，我们将对400例离散表型或前10%的定量表型进行测序，并对400例对照或后10%进行测序。其次，我们将采取第一步，通过对230名非洲裔美国人ARIC参与者进行全基因组测序，阐明一种模型表型（即HDL胆固醇）的遗传变异的暗物质，这些参与者选自HDL胆固醇分布的顶部和底部10%。将通过对其他样本进行基因分型来验证一份样本中基于序列分析的发现。专门为下一代序列数据设计的最先进的计算模型将用于质量保证、群体遗传和基因型-表型分析。由于基因组科学家、医生、流行病学家以及人口和统计遗传学家之间的持续合作，该项目的研究基础设施已经到位。该项目不仅将增强我们对具有公共卫生重要性的多种表型的遗传结构的了解，而且还将通过dbGaP提供这些序列和表型数据，使广大科学界受益。 公共卫生相关性声明： “建立在GWAS上的NHLBI疾病：美国CHARGE联盟”将利用现有资源来识别基因，这些基因是GWAS在心脏、肺和血液疾病中发现的全基因组显著和重复性良好的基础。我们将对影响15种表型的60个基因组区域进行靶向重测序（400例病例和400例对照）。第二，我们将采取第一步，通过对从HDL-胆固醇分布的顶部和底部10%中选出的230名非洲裔美国人进行全基因组测序，来阐明一种模型表型（即HDL胆固醇）的不明遗传变异的暗物质。

DESCRIPTION (provided by applicant): This research proposal, entitled "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium", will leverage existing population, laboratory and computational resources to identify susceptibility genes underlying genome-wide significant and well-replicated GWAS findings for heart, lung and blood diseases and their risk factors. The U.S. CHARGE consortium consists of multiple large population-based longitudinal cohort studies, including the Atherosclerosis Risk in Communities (ARIC) Study N=15,792, the Cardiovascular Health Study (CHS) N=5,888, and the Framingham Heart Study (FHS) N=14,428. Additionally, the Coronary Artery Risk Developments in Young Adults (CARDIA N=3,756) study has joined this collaborative effort. For each of these cohorts, DNA samples have already been isolated and the phenotype data are readily available for analysis. The proposed research will take a two pronged approach to following-up GWAS: First, we will carry-out targeted sequencing and replication genotyping in 60 genomic regions influencing 15 phenotypes. For each phenotype, we will sequence 400 cases for discrete phenotypes or the top 10% for quantitative phenotypes and 400 controls or bottom 10%. Second, we will take a first step toward illuminating the dark matter of unaccounted-for genetic variance for one model phenotype (i.e. HDL cholesterol) by whole genome sequencing of 230 African-American ARIC participants selected from the top and bottom 10% of the HDL-cholesterol distribution. Discoveries based on sequence analysis in one sample will be validated by genotyping in additional samples. State-of-the-art computational models designed specifically for next generation sequence data will be used for quality assurance, population genetic, and genotype-phenotype analyses. The research infrastructure for this project is already in place as a result of ongoing collaborations among genomic scientists, physicians, epidemiologists and population and statistical geneticists. This project will not only enhance our understanding of the genetic architecture of multiple phenotypes of public health importance, but it will also benefit the broad scientific community by making these sequence and phenotype data available via dbGaP. Public Health Relevance Statement: "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium" will leverage existing resources to identify genes underlying genome-wide significant and well-replicated GWAS findings for heart, lung and blood diseases. We will carry-out targeted resequencing (400 cases and 400 controls) in 60 genomic regions influencing 15 phenotypes. Second, we will take a first step toward illuminating the dark matter of unaccounted-for genetic variance for one model phenotype (i.e. HDL cholesterol) by whole genome sequencing of 230 African-Americans selected from the top and bottom 10% of the HDL-cholesterol distribution.