Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk

描述（由申请人提供）：心血管疾病（CVD）仍然是美国死亡的主要原因。虽然心血管疾病的风险是遗传的，但在风险途径中的致病基因的鉴定一直很缓慢。该项目通过对定量内表型的遗传解剖，包括颈动脉壁厚度、脂质、肥胖相关表型、血压相关表型、胰岛素/葡萄糖轴、炎症标志物、氧化应激标志物、凝血/凝血因子，以及与CVD风险遗传相关的脑白质高信号的测量，重点鉴定影响CVD易感性变异的因果基因。我们将利用现有的样本/数据从一个有价值的遗传资源，圣安东尼奥家庭研究（SAFS），涉及墨西哥裔美国人个体的大扩展谱系。这个长期运行的非常成功的项目已经产生了大量与心血管疾病风险相关的数量性状位点（QTL）定位。在这个项目中，我们从QTL定位转向因果基因鉴定。我们发现cvd风险基因的方法是全面的；我们将利用全基因组测序来捕获来自45个大谱系的1,957个个体的所有可能的功能变异。要使用的大型谱系代表了检测罕见功能变异的最佳研究设计。将采用先进的统计遗传学方法来确定影响心血管疾病风险的数量性状位点（QTL）区域可能的因果基因/变异。为了实现我们的目标，我们将(1)使用新的谱系特异性定位方法定位由于罕见功能变异而导致的额外CVD相关qtl，(2)获得1,957名墨西哥裔美国人的全基因组序列信息，(3)使用WGS信息确定影响CVD风险的现有qtl的因果基因。(4)使用非同义编码变体进行不可知的全基因组直接关联扫描，以识别影响心血管疾病风险的新型罕见功能蛋白改变变体；(5)使用一种新型全基因组测定方法来测量变异特异性功能调控潜力，允许使用预测的功能变体进行全基因组直接关联扫描，以识别影响心血管疾病风险的新型罕见调控变体。鉴于心血管疾病对死亡率的巨大影响和这种疾病带来的经济负担，很明显，有必要采用新的基因组分析方法来识别与疾病风险有关的新基因和途径。该项目的结果应确定心血管疾病风险的致病基因。对致病基因的鉴定将专门对这些基因的通路产生影响，并将直接确定新的药物靶点。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains the leading cause of death in the United States. Although CVD risk is heritable, identification of causal genes in risk pathways has been slow. This project focuses on the identification of causal genes that influence variation in susceptibility to CVD by concentrating on genetic dissection of quantitative endophenotypes including carotid wall thickness, lipids, obesity-related phenotypes, blood pressure-related phenotypes, the insulin/glucose axis, inflammatory markers, oxidative stress markers, hemostasis/coagulation factors, and measures of brain white matter hyperintensities that are genetically correlated with CVD risk. We will utilize existing samples/data from a valuable genetic resource, the San Antonio Family Study (SAFS), involving large extended pedigrees of Mexican American individuals. This long- running highly successful project has produced a large number of quantitative trait locus (QTL) localizations of relevance for CVD risk. In this project, we move from QTL localization to causal gene identification. Our approach to CVD-risk gene discovery is comprehensive; we will utilize whole genome sequencing to capture all possible functional variants in 1,957 individuals from 45 large pedigrees. The large pedigrees to be used represent an optimal study design for the detection of rare functional variants. Advanced statistical genetic methods will be employed to identify the likely causal genes/variants in quantitative trait locus (QTL) regions influencing CVD risk. To achieve our objectives, we will (1) localize additional CVD-related QTLs due to rare functional variants using novel pedigree-specific localization methods, (2) obtain whole genome sequence information for 1,957 Mexican American individuals, (3) identify causal genes underlying existing QTLs influencing CVD risk using WGS information, (4) perform agnostic genome-wide direct association scans using non-synonymous coding variants to identify novel rare functional protein-altering variants influencing CVD risk and, (5) use a novel whole genome assay measuring variant-specific functional regulatory potential to permit genome-wide direct association scans using the predicted functional variants to identify novel rare regulatory variants influencing CVD risk. Given the enormous impact of CVD to mortality rates and the economic burden this disease imposes, it is clear that new methods of genomic analysis are necessary to enable the identification of novel genes and pathways involved in disease risk. The results of this project should identify causal genes underlying CVD risk. Identification of the causal genes will obligately generate on the pathways of these genes and will directly identify novel drug targets.