Genomics of Cardiac Electrical Activity and Arrhythmia

描述（由申请人提供）：体表心电图上的心脏电活动反映心肌去极化和传导（PR和QRS间期）以及复极（QT间期）。心脏传导和复极异常可导致心律失常和不良结局（房颤和心源性猝死），并且可能需要放置心脏起搏器和/或除颤器。确定心脏电活动的分子决定因素将提供对心律失常产生的深入了解，并可能有助于开发新的治疗方法。 心脏电活动和心律失常的等位基因结构目前尚不清楚，但可能涉及具有中等影响的常见变体和具有较强影响的罕见变体的聚集。虽然调节区域的变化可能在心律失常中起作用，但很明显， 外显子区域的变异改变了蛋白质的分子结构，可导致蛋白质功能的改变并影响下游表型。事实上，编码区突变可导致孟德尔形式的心脏电异常，然后导致临床心律失常（例如长QT综合征和短QT综合征、进行性心脏传导疾病）。因此，我们假设生物功能编码区的遗传变异将与心脏电活动和心律失常在一般人群。首先，我们建议系统地研究心脏电活动与编码区基因变异的相关性，研究对象为来自人群研究的约45，000名个体。其次，我们将通过检查它们与以下疾病的相关性来评估所鉴定的变异的临床相关性： 心房颤动和心脏性猝死。最后，我们将评估的生物机制， 鉴定的基因和功能解剖的作用，使用小鼠和斑马鱼模型确定的变体。我们的最终目标是确定临床相关和生物学功能的基因和遗传变异，因此可能成为新疗法的靶点。 该申请代表了多中心协作努力，以有效地联合收割机结合临床和分子心脏病学，基因组学和统计遗传学，心血管和遗传流行病学，系统生物学和生物信息学以及动物模型功能研究的专业知识。我们利用现有的表型数据从8个人口为基础的心血管疾病的研究与外显子组全基因分型数据在这些研究中可用的外显子组芯片，以有效地和具有成本效益的检查功能编码区变异的关联与心脏电活动和心律失常的风险的变化。重要的是，我们将这些遗传关联转化为功能研究，以了解所鉴定的基因和变体在心脏电生理学和心律失常中的作用。

DESCRIPTION (provided by applicant): Cardiac electrical activity on the surface electrocardiogram reflects myocardial depolarization and conduction (PR and QRS intervals), and repolarization (QT interval). Abnormalities in cardiac conduction and repolarization can lead to cardiac arrhythmias and adverse outcomes (atrial fibrillation and sudden cardiac death) and can necessitate the placement of cardiac pacemakers and / or defibrillators. Identifying the molecular determinants of cardiac electrical activity will provide insight into arrhythmia generation and potentially help target the development of novel therapies. The allelic architecture of cardiac electrical activity and arrhythmias is currently unknown, but is likely to involve both common variants with modest effects and an aggregation of rare variants with stronger effects. While variation in regulatory regions may have a role in arrhythmias, it is clear that variants in exonic regions that change the molecular structure of a protein can lead to alteration in protein function and influence downstream phenotypes. Indeed, coding region mutations can lead to Mendelian forms of cardiac electrical abnormalities that then lead to clinical arrhythmias (e.g. long and short QT syndromes, progressive cardiac conduction disease). We therefore hypothesize that biologically functional coding region genetic variation will be associated with cardiac electrical activity and arrhythmia in the general population. First we propose to systematically investigate the association of cardiac electrical activity with geneti variation in coding regions in ~45,000 individuals from population-based studies. Second, we will evaluate the clinical relevance of the identified variants by examining their association with atrial fibrillation and sudden cardiac death. Finally, we will assess the biologic mechanism of the identified genes and functionally dissect the role of the variants identified using mouse and zebrafish models. Our ultimate goal is to identify genes and genetic variation that are clinically relevant and biologically functional, and therefore potentially the target of new therapies. This application represents a multi-center collaborative effort to efficiently combine expertise in clinical and molecular cardiology, genomics and statistical genetics, cardiovascular and genetic epidemiology, systems biology and bioinformatics, and animal model functional studies. We leverage existing phenotype data from eight population-based studies of cardiovascular diseases with exome-wide genotyping data from the Exome chip available in these studies, in order to efficiently and cost-effectively examine association of functional coding region variants with variation in cardiac electrical activity and risk of arrhythmias. Importantly, we then translae these genetic associations into functional studies, to understand the role in cardiac electrophysiology and arrhythmias played by the genes and variants identified.