TOPMed WGS and Molecular Epidemiology Analyses for Cardiac Hypertrophy Phenotypes

心脏肥大表型的 TOPMed WGS 和分子流行病学分析

• 批准号: 10930193
• 负责人: ULRICH BROECKEL
• 金额: $ 80.79万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930193
• 关键词: Affect; Applications Grants; Biological; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell model; Cells; Cessation of life; Clinical Research; Collection; Complex; Congestive Heart Failure; Data; Data Analyses; Data Set; Diabetes Mellitus; Disease; Disease model; Echocardiography; Funding; Genes; Genetic; Genetic Diseases; Genetic study; Genome; Genomics; Heart Hypertrophy; Heart failure; Human; Hypertension; Individual; Left Ventricular Hypertrophy; Left Ventricular Mass; Methodology; Methods; Modeling; Modification; Molecular; Molecular Epidemiology; Morbidity - disease rate; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Nature; Network-based; Pathway Analysis; Pathway interactions; Phenotype; Research Personnel; Risk; Risk Factors; Role; Sampling; Signal Transduction; Site-Directed Mutagenesis; Technology; Testing; Trans-Omics for Precision Medicine; Variant; Work; candidate identification; candidate selection; cardiovascular risk factor; cell type; cohort; differentiation protocol; disease phenotype; disorder risk; epidemiology study; exome; exome sequencing; experimental study; genetic epidemiology; genetic variant; genome sequencing; genome wide association study; human disease; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; innovation; insight; knockout gene; mortality; novel; programs; public database; screening; whole genome

PROJECT SUMMARY/ABSTRACT Left ventricular hypertrophy (LVH) represents one of the most potent risk factors for cardiovascular disease (CVD), including ischemic heart disease, chronic heart failure, and cardiovascular death. The risk of LVH is determined in part by genetic factors and results from Genome-wide Association Studies (GWAS) and Whole Exome Sequencing (WES) already identified some distinct variants and genes. Recently, the NHLBI TOPMed program has been generating one of the largest Whole Genome Sequencing (WGS) data sets. Our proposal builds on over 26,000 WGS samples from most of the large CV cohorts with relevant echocardiographic structural phenotypes. We will utilize association results from these extensive datasets as they will provide unprecedented insights into the genetics of LVH and associated phenotypes. The next important challenge for complex disease genetics and genetic epidemiology will be to elucidate the role and function of identified WGS genes. Functional studies fundamentally rely on relevant human disease models, which capture genetic and genomic features and model the polygenic nature of complex disease phenotypes. Human induced pluripotent stem cells (hiPSCs) provide a ‘human in a dish’ platform to study genome function. For this application, we will focus on analyzing the effects of novel WGS gene variants for LVH and associated structural cardiac phenotypes by using hiPSCs for functional molecular epidemiology and network prioritization-based approaches. We expand on our previous work and propose to functionally test and annotate a subset of significant WGS association signals for selected candidate genes and variants using genome and gene editing in hiPSCs and derived cardiomyocytes. Genes will be selected using on a prioritization-based approach to identify high impact variants. We will also further refine and develop approaches for network-based expression data analyses. Subsequently, we will use expression-based network concepts to describe cellular mechanisms and provide functional annotations for specific WGS genes and variants. In combination, our molecular epidemiology approach is an innovative method to the functional analysis of WGS association signals.

项目摘要/摘要 左心室肥大（LVH）代表心血管疾病的最潜在危险因素之一 （CVD），包括缺血性心脏病，慢性心力衰竭和心血管死亡。 LVH的风险是 部分由遗传因素和全基因组关联研究（GWAS）和整个的结果确定 外显子组测序（WES）已经确定了一些不同的变体和基因。 最近，NHLBI最高的程序已经生成了最大的整个基因组测序之一 （WGS）数据集。我们的提案以大多数大型简历队列的26,000多个WGS样本为基础 相关的超声心动图结构表型。我们将利用这些广泛的关联结果 数据集将对LVH和相关表型的遗传学提供前所未有的见解。这 复杂疾病遗传学和遗传流行病学的下一个重要挑战将是阐明角色 和已识别的WGS基因的功能。功能研究从根本上依赖相关的人类疾病 模型，捕获遗传和基因组特征，并建模复杂疾病的多基因性质 表型。人类诱导的多能干细胞（HIPSC）为研究提供了“人类”平台 基因组功能。对于此应用，我们将专注于分析新型WGS基因变体的影响 通过使用HIPSC进行功能分子流行病学和相关的结构心脏表型 基于网络优先级的方法。 我们扩展了我们以前的工作和建议，以在功能上测试和注释重要的WG的子集 使用基因组和基因编辑在HIPSC和基因编辑的相关信号和变体中 衍生的心肌细胞。将使用基于优先级的方法选择基因以识别高影响 变体。我们还将进一步完善并开发用于基于网络的表达数据分析的方法。 随后，我们将使用基于表达的网络概念来描述细胞机制并提供 特定WGS基因和变体的功能注释。结合我们的分子流行病学 方法是WGS关联信号功能分析的创新方法。