Comprehensive Sequencing and Analysis of Variation in NHLBI Cohorts

描述（由申请人提供）：我们建议创建表型样本中最大的DNA序列变异目录，并开创这种深度和规模的数据在关键心血管表型分析中的应用。我们建议通过（1）进行全面测序（在基因组或外显子组范围内，如与项目指导委员会合作确定的）在10，000个表型样本中的每一个中;（2）在20，000个额外的样品中快速基因分型初始组的新变体，和（3）向研究团体提供原始数据，注释的变体，以及用于变异检测、验证和与表型关联的框架。该项目的最终目标是创建一个数据和分析资源，为随后多年对广泛的心血管表型中等位基因频率变异的全谱进行后续询问奠定基础。 公共卫生相关性：拟议的项目旨在全面描述人类基因组（外显子组）中最具功能相关性和可解释性的部分的DNA序列变异，并使这些发现与NHLBI队列样本中测量的大量心血管疾病和临床表型下游相关。这将使深入检查已知的风险基因座和发现许多以前在定位研究中遗漏的新基因座成为可能-从而产生新的生物学假设，新的药物靶点和改进的临床预测。

DESCRIPTION (provided by applicant): We propose to create what will be the largest catalogue of DNA sequence variation in phenotyped samples and to pioneer the application of this depth and scale of data to the analysis of key cardiovascular phenotypes. We propose to do this by (1) performing comprehensive sequencing (on a genome- or exome-wide scale, as determined in collaboration with the Project Steering Committee) in each of 10,000 phenotyped samples; (2) rapidly genotyping an initial set of novel variants in 20,000 additional samples, and (3) making available to the research community raw data, annotated variants, and a framework for variant detection, validation and association to phenotypes. The ultimate goal of this project is to create a data and analytic resource that will lay the groundwork for subsequent interrogation of the full spectrum of allele frequency variation in a wide array of cardiovascular phenotypes for many subsequent years. PUBLIC HEALTH RELEVANCE: The proposed project aims to comprehensively describe DNA sequence variation in the most functionally relevant and interpretable portion of the human genome (the exome), and to enable downstream association of these findings to the vast collection of cardiovascular disease and clinical phenotypes measured in NHLBI cohort samples. This will make possible deep inspection of known risk loci and discovery of many new loci previously missed in mapping studies - leading to new biologic hypothesis, new drug targets, and improved clinical prediction.