WHI Sequencing Project (WHISP)

摘要妇女健康倡议测序项目（WHISP）该项目是响应NHLBI RC2主题“高表型NHLBI队列的大规模DNA测序和分子分析”（RFA-OD-09-004）而提交的，其总体目标是确定来自不同血统和地理背景的美国绝经后妇女中高优先级心肺和血液表型的假定功能变异。越来越多的全基因组关联研究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）的关联。许多这些关联在大型研究中被反复证实，被认为是“假定的真正变异”。为了将这些基因用于临床或预防用途，需要确定可能直接导致疾病易感性的罕见致病变异。事实上，顺序策略最适合描述和编录导致疾病遗传和病因的全部因果变异。为了充分研究CVD相关性状的遗传结构，我们将进行基于CVD表型的重测序，以无偏发现在妇女健康倡议（WHI）临床试验（CT） （n=68,132）和观察性研究（OS） （n=93,676）中从多个CVD相关表型分布的尾部选择的参与者子集中具有重大影响的罕见变异。然后，我们将通过在研究指导委员会选择的剩余队列和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，以完整地描述导致疾病遗传和发展的因果变异集，并进一步评估这些因果变异在其他cvd相关性状和途径中的作用。我们还将对选定的变异进行通路分析，以评估某一特定通路是否富含疾病风险相关基因。WHI是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。这个庞大而多样的研究群体不仅使我们能够识别出导致这些表型的新的罕见变异（特定目标1），而且使我们能够在剩余的队列参与者中验证这些新发现的编码变异，从而开始表征导致疾病遗传性和病因学的完整因果变异集，并进一步评估这些因果变异与其他cvd相关性状和（特定目标2）相关的作用。这项研究产生的信息对于确定任何给定的无可争议的变异对健康的影响至关重要。研究结果还可能为疾病途径和机制以及疾病筛查、预防和治疗的靶点提供有价值的见解。

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.