Building on GWAS for NHLBI-disease: the CHARGE consortium

以 NHLBI 疾病 GWAS 为基础：CHARGE 联盟

• 批准号: 7942005
• 负责人: ERIC A. BOERWINKLE
• 金额: $ 1527.28万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942005
• 关键词: Accounting; African American; American; Amino Acid Substitution; Architecture; Arts; Atherosclerosis; Base Sequence; Bioinformatics; Blood; Blood Pressure; Cardiovascular system; Cohort Studies; Collaborations; Communities; Computer Simulation; Coronary artery; DNA; DNA Resequencing; DNA Sequence Rearrangement; Data; Databases; Development; Disease; Environment; Environmental Exposure; Epidemiologist; European; Framingham Heart Study; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Health; Heart; Hematological Disease; High Density Lipoprotein Cholesterol; Individual; Individual Differences; Laboratories; Location; Lung; Metabolic Pathway; Methods; Minor; Modeling; Natural Selections; Nature; Participant; Pattern; Phenotype; Physicians; Population; Population Genetics; Public Health; Publishing; Reporting; Research; Research Infrastructure; Research Proposals; Resources; Risk; Risk Factors; SNP genotyping; Sampling; Scientist; Sequence Analysis; Site; Slide; Statistical Methods; Susceptibility Gene; Tail; Techniques; Testing; TimeLine; Variant; base; cohort; computing resources; database of Genotypes and Phenotypes; design; gene environment interaction; genome sequencing; genome wide association study; genome-wide; indexing; interest; model design; next generation; population based; public health relevance; quality assurance; stomach cardia; working group; young adult

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.

描述(由申请人提供)： 这项题为“为NHLBI疾病建立GWAS基础：美国Charge联盟”的研究计划将利用现有的人口、实验室和计算资源，以确定在全基因组范围内心脏、肺病和血液疾病及其风险因素的重要和良好复制的GWAS研究结果背后的易感基因。美国CARGE联盟由多项大型人群纵向队列研究组成，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和弗雷明翰心脏研究(FHS)N=14,428。此外，青年成人冠状动脉风险发展(CARDIA N=3,756)研究也加入了这项合作努力。对于这些队列中的每一个，DNA样本已经被分离出来，表型数据随时可以进行分析。这项拟议的研究将采取双管齐下的方法对GWAS进行后续研究：首先，我们将对影响15个表型的60个基因组区域进行靶向测序和复制基因分型。对于每一种表型，我们将对400例患者进行离散表型或前10%的定量表型排序，并对400例对照或后10%的患者进行排序。其次，我们将迈出第一步，通过对230名非裔美国ARIC参与者的全基因组测序，阐明一种模型表型(即高密度脂蛋白-胆固醇)的不明遗传差异，这些参与者来自高密度脂蛋白-胆固醇分布的顶部和底部10%。在一个样本中基于序列分析的发现将通过在其他样本中进行基因分型来验证。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-表型分析。由于基因组科学家、内科医生、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。该项目不仅将加强我们对具有公共卫生重要性的多种表型的遗传结构的理解，而且还将通过DBGaP提供这些序列和表型数据，从而使广大科学界受益。 公共卫生相关声明： “建立在用于NHLBI疾病的GWAS的基础上：美国Charge联盟”将利用现有的资源来确定在全基因组范围内心脏、肺病和血液疾病的重要和良好复制的GWAS研究结果背后的基因。我们将在影响15个表型的60个基因组区域进行有针对性的重测序(400例病例和400例对照)。其次，我们将通过对230名非洲裔美国人的全基因组测序，来阐明一种模型表型(即高密度脂蛋白-胆固醇)的不明遗传差异的暗物质，这是第一步。