WHI Sequencing Project (WHISP)

描述（申请人提供）：摘要妇女健康倡议测序项目（WHISP）该项目的总体目标是响应NHLBI RC 2主题“大规模DNA测序和良好表型NHLBI队列的分子特征分析”（RFA-OD-09-004）的目的是鉴定美国后肺癌患者中高优先级心肺和血液表型的推定功能变体。来自不同祖先和地理背景的更年期妇女。越来越多的全基因组关联研究报告了遗传变异与心肺和血液相关的复杂性状和疾病（如心血管疾病（CVD），糖尿病和肥胖症）的关联。这些关联中的许多已经在大型研究中被反复证实，并被认为是“假定的真正变体”。为了使这些基因被考虑用于临床或预防用途，需要鉴定直接导致疾病易感性的可能罕见的致病变体。事实上，序贯策略最适合于表征和编目有助于疾病遗传性和病因学的一整套因果变异。为了全面检查CVD相关性状的遗传结构，我们将进行基于CVD表型的重测序，以无偏倚地发现在女性健康倡议（WHI）临床试验（CT）（n= 68，132）和观察性研究（OS）（n= 93，676）中从多种CVD相关表型分布的尾部选择的参与者子集中具有较大影响的罕见变异。然后，我们将通过在剩余队列和研究指导委员会选择的其他人群中进行选择性基因分型来验证新发现的编码变体，以完整表征有助于疾病遗传性和发展的因果变体集，并进一步评估这些因果变体与其他CVD相关性状和途径的作用。我们还将对选定的变体进行途径分析，以评估特定途径是否富含疾病风险相关基因。WHI是对绝经后妇女健康最权威、影响最深远的基于人群的研究之一。这个庞大而多样化的研究人群不仅使我们能够识别有助于这些表型的新的罕见变异（特定目的1），但允许我们验证这些新发现的编码变异在其余的队列参与者开始表征的因果变异的完整集合有助于疾病遗传性和病因，并进一步评估这些因果变异的作用与其他CVD-相关特征和（具体目标2）。从这项研究中产生的信息将是至关重要的，以确定任何给定的无可争议的变异的健康影响。这些发现还可以为疾病的途径和机制以及疾病筛查、预防和治疗的目标提供有价值的见解。 公共卫生相关性：全基因组关联研究已经报道了遗传变异与心肺和血液相关的复杂性状和疾病如心血管疾病（CVD）、糖尿病和肥胖症的关联。为了使这些基因被考虑用于临床或预防用途，需要鉴定直接导致疾病易感性的可能罕见的致病变异。为了全面检查CVD相关性状的遗传结构，我们建议进行基于CVD表型的重测序，然后进行验证基因分型，以无偏见地发现在妇女健康倡议中具有多种CVD相关表型分布的参与者子集中具有大影响的罕见变体。

DESCRIPTION (provided by applicant): Abstract Women's Health Initiative Sequencing Project (WHISP) The overall goal of this project submitted in response to NHLBI RC2 Topic 'Large-scale DNA Sequencing and Molecular Profiling of Well-phenotyped NHLBI Cohorts' (RFA-OD-09-004) is to identify putative functional variants for high-priority heart lung and blood phenotypes among American post-menopausal women from diverse ancestral and geographic backgrounds. Increasingly, genome-wide association studies have reported associations of genetic variants with heart lung and blood related complex traits and diseases such as cardiovascular diseases (CVD), diabetes, and obesity. Many of these associations have been repeatedly confirmed in large studies and are considered "putative genuine variants". For these genes to be considered for clinical or preventive uses, identification of possible rare causal variants directly responsible for the disease- susceptibility is required. Indeed, a sequential strategy is best suited to characterize and catalogue the complete set of causal variants contributing to disease heritability and etiology. To fully examine the genetic architecture of CVD-related traits we will perform CVD phenotype-based resequencing for the unbiased discovery of rare variants having large effects in a subset of participants selected from the tails of multiple CVD related phenotypic distributions in the Women's Health Initiative (WHI) Clinical Trial (CT) (n=68,132) and Observational Study (OS) (n=93,676). We will then validate the newly discovered coding variants by performing selective genotyping in the remaining cohort and other populations selected by the study steering committee, toward a complete characterization of the set of causal variants contributing to disease heritability and development, and to further assess the role of these causal variants in relation to other CVD-related traits and pathways. We will also perform pathway analysis on selected variants to assess whether a particular pathway is enriched with disease risk-associated genes. The WHI is one of the most definitive, far-reaching population-based studies of post-menopausal women's health. This large and diverse study population not only enables us to identify novel rare variants that contribute to these phenotypes (specific aim 1) but allows us to validate these newly discovered coding variants in the remaining cohort participants to begin to characterize the complete set of causal variants contributing to disease heritability and etiology and to further assess the role of these causal variants in relation to other CVD-related traits and (specific aim 2). Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment. PUBLIC HEALTH RELEVANCE: Genome-wide association studies have reported associations of genetic variants with heart lung and blood related complex traits and diseases such as cardiovascular diseases (CVD), diabetes, and obesity. For these genes to be considered for clinical or preventive uses, identification of possible rare causal variants directly responsible for the disease-susceptibility is required. To fully examine the genetic architecture of CVD- related traits, we propose to perform CVD phenotype-based resequencing followed by validation genotyping for the unbiased discovery of rare variants having large effects in a subset of participants with multiple CVD related phenotypic distributions in the Women's Health Initiative.