Deciphering the genetic mechanisms of atrial fibrillation

房颤是一个重要且日益严重的公共卫生问题。大多数病例发生在老年人和 因此，这一问题的发生率正在上升；受房颤影响的美国人人数预计将激增至16人 到2050年将达到100万。其他临床特征包括高血压和潜在的心脏病，而许多相对 年轻患者没有明显的危险因素，被指定为“孤立性”或早发性房颤(EOAF)。田径队 由于缺乏有效的治疗方法，疫情进一步复杂化。治疗的有限成功源于 部分原因是对房颤的病理生理学认识不完全，未能针对 潜在的机制。传统上，房颤被认为是一种零星的非遗传性疾病，但我们和 其他研究表明，EOAF有很强的遗传基础。定位克隆与候选基因 方法将心脏离子通道和信号分子的突变与EOAF联系起来。而这些 研究为潜在的机制提供了重要的见解，大多数罕见的变异 对EOAF的易感性仍不清楚。鉴于下一代测序(NGS)的最新进展， 在其他心血管表型中发现新基因和我们的初步数据，这是首要目标 这一建议的目的是使用NGS来识别新的AF基因并破译其潜在的遗传机制 EOAF。我们的临床DNA登记系统地登记了来自不同种族的60多个家庭 背景：早发性家族性房颤。我们建议使用这一规模庞大且特征良好的队列来解决 两个具体目标：目标1将进行多层次逐步方法来识别罕见的相关遗传变异 与EOAF合作。第一个完整的外显子组测序(WES)将在我们现有的60个EOAF家庭中进行，他们确实 不包含候选基因变异，以识别基于稀有性、种族、共同分离的罕见变异 AF，预测致病性和生物信息学过滤。其次，最有希望的变种将在 AFGen Consortium TOPMed队列中，超过3,500名患有EOAF的先证者和3,500名对照 进行全基因组测序(WGS)。这一目标建立在我们发布的研究基础上，在该研究中，我们确定了 应用WES方法的五个新的候选AF基因和最近在EOAF中成功完成的WGS TOPMed队列中的先驱。AIM 2将通过以下方式确定EOAF的潜在遗传机制 用体外电生理学和体内功能研究高优先级稀有变异体的功能 斑马鱼中的化验能够使疾病联系在一起。这个目标建立在我们已有的先前工作的基础上 WES鉴定的钙通道基因中一个罕见的房颤连锁突变体的功能特征 调节斑马鱼心脏传导的发育基因。这些研究不仅将确定小说 并提供了对EOAF潜在遗传机制的见解，但也将发现新的 房颤的治疗方法。它们也代表了开发特定于子类型的第一步 针对这种常见和病态的疾病的基于机制的治疗。

Atrial fibrillation (AF) is an important and increasing public health problem. Most cases occur in the elderly and so the incidence of the problem is rising; the number of Americans affected with AF is expected to surge to ~16 million by 2050. Other clinical features include hypertension and underlying heart disease while many relatively young patients have no apparent risk factors and are designated as “lone” or early-onset AF (EOAF). The AF epidemic is further complicated by the lack of effective therapies. The limited success of treatments stems in part from an incomplete understanding of the pathophysiology of AF and failure to target therapy to the underlying mechanisms. Traditionally, AF was considered to be a sporadic, non-genetic disorder but we and others have shown that EOAF has a substantial genetic basis. Positional cloning and candidate gene approaches have linked mutations in cardiac ion channels, and signaling molecules with EOAF. While these studies have provided important insights into underlying mechanisms, most of the rare variation in susceptibility to EOAF remains unknown. Given recent advances in next generation sequencing (NGS), discovery of novel genes in other cardiovascular phenotypes and our preliminary data, the overarching goal of this proposal is to use NGS to identify novel AF genes and decipher the underlying genetic mechanisms of EOAF. Our clinical-DNA registries have systematically enrolled over 60 families from diverse ethnic background with early-onset familial AF. We propose to use this large and well-characterized cohort to address two specific aims: Aim 1 will conduct a multi-tiered stepwise approach to identify rare genetic variants linked with EOAF. First whole exome sequencing (WES) will be performed in our existing 60 EOAF families, who do not harbor candidate gene variants, to identify rare variants predicated on rarity, ethnicity, co-segregation with AF, predicted pathogenicity and bioinformatics filtering. Second, the most promising variants will replicated in AFGen Consortium TOPMed Cohort in which over 3,500 probands with EOAF and 3,500 controls have undergone whole genome sequencing (WGS). This aim builds on our published study in which we identified five novel candidate AF genes using a WES approach and the recent successful completion of WGS in EOAF probands in the TOPMed Cohort. Aim 2 will determine the underlying genetic mechanisms of EOAF by functionally characterizing high priority rare variants using in vitro electrophysiology and in vivo functional assays in zebrafish to enable disease-association. This aim builds upon our prior work where we have functionally characterized a rare AF-linked variant in the Ca channel gene identified by WES and identified rare developmental genes that modulate cardiac conduction in zebrafish. These studies will not only identify novel AF genes and provide insights into underlying genetic mechanisms of EOAF but will also uncover novel therapeutic approaches for AF. They also represent the first step in the development of sub-type specific mechanism-based therapies for this common and morbid condition.