Genomics of Cardiac Arrhythmias

项目摘要 心律失常是普遍存在的，并与大量的发病率和医疗保健利用。在 特别是，室上性心动过速和心动过缓是心悸的常见原因， 晕厥，在某些情况下可能导致猝死。这些疾病的许多治疗方法 不完全有效或与潜在不良反应相关。尽管公认的公共卫生 心律失常的重要性，对其机制的了解有限。 我们的总体目标是确定心律失常的原因，并改善对受影响患者的治疗。 该提案的具体目标是利用大规模人类遗传关联研究， 了解室上性心动过速和缓慢性心律失常的机制。该提案 是由三个关键的观察所激发的。 首先，单基因型室上性心动过速和缓慢性心律失常， 这些心律失常，以及识别与这些条件相关的常见变异的初步数据， 表明室上性心动过速和缓慢性心律失常有很大遗传基础。然而 全基因组关联研究是一种了解人类疾病的高效方法， 了以下条件第二，我们在协作遗传关联分析方面有丰富的经验， 心律失常，并建立了心律失常遗传学（代理）网络，一个多站点的联盟， 研究人员将为拟议的目标提供样本。第三，我们的团队是由专家组成， 复杂性状和心律失常遗传学，他们开发了创新方法， 鉴定的遗传基因座的表征。 申请人是具有心律失常遗传学经验的早期研究者。目标1和2 在目前的建议中，我们将确定与室上性心动过速相关的遗传易感性位点， 和缓慢性心律失常，通过在特征良好的个体中进行全基因组关联研究。在aim中 我们将量化室上性心动过速和缓慢性心律失常的总遗传贡献， 系统地评估这些心律失常的遗传结构，并估计 心律失常和相关表型。在目标4中，我们将通过描述 干细胞室上性心动过速和缓慢性心律失常基因的电生理表型 细胞衍生的心肌细胞，斑马鱼模型系统，并通过细胞电生理学。 我们预计，我们的多方面方法将有助于更好地了解 心律不齐这些见解可能会导致新的治疗方法，患者管理和 对与更广泛的科学界相关的心血管生物学的全面理解。

Project summary Cardiac arrhythmias are prevalent and are associated with substantial morbidity and healthcare utilization. In particular, supraventricular tachycardias and bradyarrhythmias are common causes of palpitations and syncope, and may lead to sudden death in some circumstances. Many treatments for these conditions are incompletely effective or associated with potential adverse effects. Despite the recognized public health importance of arrhythmias, there is a limited understanding of their mechanisms. Our overall goals are to identify the causes of arrhythmias and improve treatments for affected patients. The specific objective of this proposal is to leverage large-scale human genetic association studies to understand the mechanisms of both supraventricular tachycardias and bradyarrhythmias. The proposal is motivated by three key observations. First, monogenic forms of supraventricular tachycardias and bradyarrhythmias, familial aggregation of these arrhythmias, and preliminary data identifying common variation associated with these conditions all indicate that there is a substantial genetic basis for supraventricular tachycardias and bradyarrhythmias. Yet genome-wide association studies, a highly efficient method for understanding human disease, are lacking for these conditions. Second, we have substantial experience with collaborative genetic association analyses of arrhythmias, and have established the Arrhythmia GENetics (AGENT) neTwork, a multi-site consortium of investigators that will contribute samples for the proposed aims. Third, our team is comprised of experts in complex trait and arrhythmia genetics who have developed innovative methods to enable functional characterization of identified genetic loci. The applicant is an Early Stage Investigator with experience in arrhythmia genetics. In Aims 1 and 2 of the current proposal, we will identify genetic susceptibility loci associated with supraventricular tachycardias and bradyarrhythmias by performing genome-wide association studies in well-characterized individuals. In Aim 3 we will quantify the aggregate genetic contributions to supraventricular tachycardias and bradyarrhythmias, systematically assess the genetic architecture of these arrhythmias, and estimate the genetic correlation of arrhythmias and related phenotypes. In Aim 4, we will move from association to mechanism by characterizing the electrophysiological phenotype of the top supraventricular tachycardia and bradyarrhythmia genes in stem cell-derived cardiomyocytes, a zebrafish model system, and by cellular electrophysiology. We anticipate that our multi-faceted approach will facilitate an improved understanding of the causes of arrhythmias. Such insights may lead to novel therapeutic approaches for patient management and a comprehensive understanding of cardiovascular biology relevant to the broader scientific community.