Using Genetics to Inform Mechanism of Cardiovascular Disease

利用遗传学了解心血管疾病的机制

• 批准号: 10352380
• 负责人: Cristen J Willer
• 金额: $ 90.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352380
• 关键词: Aortic Aneurysm; Atrial Fibrillation; Bioinformatics; Biological; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinical; Computing Methodologies; Coronary Arteriosclerosis; Data; Development; Diagnosis; Disease; Dissection; Genes; Genetic; Genetic study; Genomics; Goals; Lipids; Myocardial Infarction; Pharmacotherapy; Phenotype; Preventive; Sampling; Signal Transduction; Statistical Methods; Technology; Testing; Therapeutic; United States; Variant; Work; cardiovascular disorder prevention; case control; epigenomics; genetic variant; genome wide association study; improved; innovation; insertion/deletion mutation; insight; loss of function; novel; novel therapeutics; targeted sequencing; trait; whole genome

PROJECT SUMMARY/ABSTRACT The goal of this R35 proposal is to uncover novel genetic discoveries and biological mechanisms underlying association with devastating cardiovascular diseases. This proposal builds on strengths in high-throughput genetics and genomics and development and application of innovative computational and statistical methods and genomics technology to maximize the benefits of genetic studies of cardiovascular disease. We will continue our discovery efforts to uncover genetic variants associated with a variety of cardiovascular diseases including atrial fibrillation, aortic aneurysm and dissection, and myocardial infarction and coronary artery disease. Building on our previous work where we identified a number of new genes for coronary artery disease and lipids, we also propose to uncover the mechanisms underlying association at known loci using genetics and epigenomics. We propose to assess the phenotypic impact of the ~19 million variants and 20k indels and SVs identified from whole genome sequenced samples by imputing them into 70,000 new GWAS samples with many cardiovascular phenotypes. We will perform integrated analyses with epigenomics data to highlight clusters of loci with related function. We also propose to perform targeted sequencing of 300 genes in 30,000 CAD cases and controls to search for loss of function variants at CAD loci that implicate CAD genes. We will continue to search for mechanistic insight by performing a PheWAS for all CAD-associated variants identified, disentangling multiple independent signals and correlated traits and clinical endpoints using conditional testing. Completion of these studies will provide new insights into disease mechanisms that have the potential to catalyze breakthroughs in cardiovascular disease prevention, treatment, and diagnosis.

项目总结/摘要 这项R35提案的目标是揭示新的遗传发现和潜在的生物学机制。 与毁灭性的心血管疾病有关。这一建议建立在高通量的优势之上 遗传学和基因组学以及创新计算和统计方法的开发和应用 和基因组学技术，以最大限度地发挥心血管疾病基因研究的效益。 我们将继续努力发现与各种心血管疾病相关的遗传变异， 疾病包括心房颤动、主动脉瘤和夹层、心肌梗死和冠状动脉 动脉疾病在我们之前的工作基础上，我们确定了一些新的冠状动脉基因， 疾病和脂质，我们还建议揭示潜在的机制，在已知的基因座使用 遗传学和表观基因组学。我们建议评估约1900万个变异和20000个变异的表型影响。 通过将全基因组测序样本中的插入缺失和SV输入到70，000个新的GWAS中， 具有多种心血管表型的样本。我们将对表观基因组学数据进行综合分析， 突出显示具有相关功能基因座簇。我们还建议对300个基因进行靶向测序 在30，000例CAD病例和对照中寻找涉及CAD基因的CAD基因座的功能缺失变体。 我们将继续通过对所有CAD相关变体执行PheWAS来寻找机制见解 识别，解开多个独立的信号和相关的性状和临床终点， 条件测试 这些研究的完成将为疾病机制提供新的见解， 促进心血管疾病预防、治疗和诊断的突破。