Genomics of Cardiac Arrhythmias

项目总结 心律失常很普遍，并与相当大的发病率和医疗保健利用有关。在……里面 具体地说，室上性心动过速和缓慢性心律失常是心悸和 晕厥，在某些情况下可能导致猝死。针对这些情况的许多治疗方法是 不完全有效的或与潜在的不利影响有关的。尽管公认的公共卫生 由于心律失常的重要性，人们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，并改进对受影响患者的治疗。 这项提案的具体目标是利用大规模的人类遗传关联研究来 了解室上性心动过速和缓慢性心律失常的机制。这项建议 是由三个关键的观察结果推动的。 首先，单基因形式的室上性心动过速和缓慢性心律失常，家族聚集性 这些心律失常，以及识别与这些情况相关的常见变异的初步数据都是 提示室上性心动过速和缓慢性心律失常有其坚实的遗传基础。还没有 全基因组关联研究是了解人类疾病的一种高效方法，但缺乏 这些条件。其次，我们在协作遗传关联分析方面拥有丰富的经验 心律失常，并建立了心律失常遗传学(代理)网络，一个多地点联盟 将为拟议的目标提供样本的调查人员。第三，我们的团队由以下方面的专家组成 复杂的性状和心律失常遗传学，他们开发了创新的方法，使功能 已识别的遗传基因座的特征。 申请者是具有心律失常遗传学经验的早期研究人员。在目标1和目标2中 根据目前的建议，我们将确定与室上性心动过速相关的遗传易感基因。 通过在特征良好的个体中进行全基因组关联研究来研究缓慢性心律失常。在AIM 3我们将量化室上性心动过速和缓慢性心律失常的总体遗传贡献， 系统地评估这些心律失常的遗传结构，并估计 心律失常及相关表型。在目标4中，我们将通过特征描述从关联转移到机制 脑干顶端室上性心动过速和缓慢性心律失常基因的电生理表型 细胞来源的心肌细胞，斑马鱼模型系统，以及细胞电生理学。 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。这样的见解可能会导致新的治疗方法用于患者管理和 全面了解与更广泛的科学界相关的心血管生物学知识。

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.