Whole-genome sequencing analysis of coronary atherosclerosis and related traits

冠状动脉粥样硬化及相关性状的全基因组测序分析

• 批准号: 10569647
• 负责人: PAUL STEFAN DE VRIES
• 金额: $ 74.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569647
• 关键词: African ancestry; Arterial Fatty Streak; Atherosclerosis; Biological; Cardiovascular system; Carotid Artery Plaques; Categories; Clinical; Code; Complex; Coronary Arteriosclerosis; Coronary artery; Data; Data Set; Data Sources; Deposition; Disease; European ancestry; Event; Frequencies; Gene Frequency; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Heritability; Imaging Techniques; Individual; Knowledge; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; Nucleic Acid Regulatory Sequences; Participant; Pathway interactions; Phase; Phenotype; Population; Predisposition; Prevention; Primary Prevention; Procedures; Progressive Disease; Public Health; Resources; Scanning; Single Nucleotide Polymorphism; Technology; Testing; Trans-Omics for Precision Medicine; Translating; Ultrasonography; United States; Untranslated RNA; Variant; Vascularization; X-Ray Computed Tomography; cardiometabolism; cardiovascular risk factor; carotid intima-media thickness; compare effectiveness; coronary artery calcification; design; effectiveness testing; exome sequencing; genetic architecture; genetic risk factor; genetic variant; genome resource; genome sequencing; genome wide association study; genomic locus; improved; insight; large scale data; mortality; outcome prediction; pleiotropism; polygenic risk score; precision medicine; programs; rare variant; risk prediction; tool; trait; whole genome

PROJECT SUMMARY Genome-wide association studies have identified common single nucleotide variants at over 160 genetic loci associated with coronary artery disease (CAD) and subclinical atherosclerosis (coronary artery calcification, carotid intima media thickness, and carotid plaque). These discoveries have led to important insights into the pathways that contribute to subclinical atherosclerosis and CAD, as well as insights into the genetic architecture of atherosclerosis. For example, the heritability explained by common genetic variants for CAD appears to be concentrated in regulatory regions. Nevertheless, neither the genome-wide association studies nor exome sequencing studies performed to date have been able to examine both coding and non-coding variants across the allele frequency spectrum in relation to subclinical atherosclerosis and CAD. Furthermore, these studies have largely focused on European ancestry participants. Approaches that identify pleiotropic loci or quantify genetic correlation among phenotypes exist, but have not yet been applied to subclinical atherosclerosis and CAD. Genetic risk prediction studies based on common variants show promise with regards to improving primary prevention, but the extent to which adding low-frequency and rare variants to polygenic risk scores improves risk prediction is not known, nor have scores been developed and tested in those of non-European ancestry. A wealth of whole-genome sequencing (WGS) data has been generated by initiatives such as the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and the National Human Genome Research Institute (NHGRI) Centers for Common Disease Genomics (CCDG) program in populations from different ancestries. To expand our knowledge of genetic factors contributing to CAD and subclinical atherosclerosis phenotypes, we propose to use WGS data from TOPMed and CCDG (up to 101,295 individuals from diverse ancestries, of which 58% are non-European ancestry), with extended genomic coverage of low-frequency and rare genetic variants as well as more complex genetic variants such as structural variants. Findings from the WGS analysis will be replicated in several large-scale data sources, including exome sequencing data and genotype data imputed using TOPMed as the reference panel. Thus, we will examine genetic variation that has so far been missed, including structural variants. We will leverage the results of these analyses to explore the genetic architecture of subclinical atherosclerosis and CAD, investigate pleiotropy and genetic correlation between subclinical atherosclerosis and CAD and related cardiovascular traits, as well as assess the contribution of low-frequency and rare variants to risk prediction of CAD. Finally, we will create and test a polygenic risk score designed specifically for African ancestry population. This proposal brings together large-scale WGS datasets, clinical and subclinical atherosclerosis phenotypes, and exploits advances in genomic technologies and computational approaches. In doing so, we will advance the realization of precision medicine for CAD.

项目概要 全基因组关联研究已鉴定出 160 多个基因位点的常见单核苷酸变异 与冠状动脉疾病（CAD）和亚临床动脉粥样硬化（冠状动脉钙化， 颈动脉内膜中层厚度和颈动脉斑块）。这些发现使人们对以下问题有了重要的认识： 导致亚临床动脉粥样硬化和 CAD 的途径，以及对遗传结构的深入了解 动脉粥样硬化。例如，用 CAD 的常见遗传变异来解释的遗传力似乎是 集中在监管区域。然而，全基因组关联研究和外显子组研究都没有 迄今为止进行的测序研究已经能够检查编码和非编码变异 与亚临床动脉粥样硬化和 CAD 相关的等位基因频谱。此外，这些研究 主要关注欧洲血统的参与者。识别多效性基因座或量化的方法 表型之间存在遗传相关性，但尚未应用于亚临床动脉粥样硬化和 计算机辅助设计。基于常见变异的遗传风险预测研究显示出改善初级疾病的希望 预防，但在多基因风险评分中添加低频和罕见变异可在多大程度上提高风险 预测结果尚不清楚，也没有在非欧洲血统的人中开发和测试分数。 国家心脏中心等倡议已经生成了大量的全基因组测序（WGS）数据， 肺和血液研究所 (NHLBI) 精准医学跨组学 (TOPMed) 计划和国家 人类基因组研究所 (NHGRI) 常见疾病基因组学中心 (CCDG) 项目 来自不同血统的人群。扩大我们对导致 CAD 的遗传因素的了解 亚临床动脉粥样硬化表型，我们建议使用来自 TOPMed 和 CCDG 的 WGS 数据（多达 101,295 来自不同血统的个体，其中 58% 是非欧洲血统），具有扩展的基因组覆盖范围 低频和罕见的遗传变异以及更复杂的遗传变异（例如结构变异）。 WGS 分析的结果将在多个大规模数据源中得到复制，包括外显子组 使用 TOPMed 作为参考组估算测序数据和基因型数据。因此，我们将检查 迄今为止被忽视的遗传变异，包括结构变异。 我们将利用这些分析的结果来探索亚临床动脉粥样硬化的遗传结构 和 CAD，研究亚临床动脉粥样硬化与 CAD 及相关疾病之间的多效性和遗传相关性 心血管特征，以及评估低频和罕见变异对风险预测的贡献 计算机辅助设计。最后，我们将创建并测试专门为非洲血统人群设计的多基因风险评分。 该提案汇集了大规模 WGS 数据集、临床和亚临床动脉粥样硬化表型、 并利用基因组技术和计算方法的进步。在此过程中，我们将推进 CAD精准医疗的实现。