Identification of Common Genetic Variants for Atrial Fibrillation and PR Interval

描述(申请人提供)：房颤(房颤)是最常见的心律失常。预计到2050年，它将影响600-1200万美国人。房颤是一个主要的公共卫生负担，与中风风险增加5倍，痴呆症风险增加一倍，心力衰竭风险增加两倍，死亡率增加近2倍有关。据估计，房颤造成的医疗保健超额费用每年近260亿美元。房颤被认为是可遗传的，近年来，通过全基因组关联研究，已经确定了房颤的3个遗传位点。最近，我们完成了一项全基因组研究的大型荟萃分析，确定了6个新的房颤基因座。我们将在之前工作的基础上，使用多学科方法，整合所有9个房颤Gwas基因座的定向测序，在Charge房颤联合体中进行健壮的复制，以及基于模型系统的功能分析。我们将利用来自弗雷明翰心脏研究和马萨诸塞州综合医院的两个具有良好特征的早发性房颤队列。具体地说，我们建议：1)通过分析美国国立卫生研究院重测序和基因分型服务在480名早发性房颤患者和480名参照者中生成的房颤前5个基因座的现有靶向测序数据，以及通过对相同受试者中另外4个房颤基因座进行新的靶向测序，识别已发表的9个GWAS基因座的潜在致病遗传变异。2)在5,776例独立房颤病例和9,229名参照者中复制我们目标测序项目中发现的前400个MAF&>0.5%的房颤变异，并在1,000名早发性房颤和1,000名参照者中复制前3个基因区域的罕见和单一SNPs(MAF&lt；0.5%)。3)通过使用细胞电生理学来描述离子通道中的编码变异，并结合斑马鱼、小鼠和基于细胞的检测来检查两个最有希望的房颤相关基因座上的非编码变异，从功能上评估新发现的房颤遗传变异。我们的翻译方法将有助于更好地了解这种常见和病理性心律失常的分子基础。识别致病变种可以加强风险分层，并将为更广泛的科学界和医药界的药物发现提供预防和治疗目标。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common arrhythmia. It is expected to affect 6-12 million Americans by 2050. AF is a major public health burden, associated with a 5-fold increased stroke risk, doubling in dementia risk, tripling in heart failur risk and nearly 2-fold increase in mortality. The estimated excess cost of health care due to AF is nearly $26 billion annually. AF is known to be heritable, and in recent years, 3 genetic loci fo AF have been identified through genome-wide association studies. More recently, we completed a large meta-analysis of genome-wide studies and identified 6 novel loci for AF. We will build upon our prior work using a multidisciplinary approach that integrates targeted sequencing of all 9 AF GWAS loci, robust replication in the CHARGE AF Consortium, and model system based functional analyses. We will take advantage of two well- characterized cohorts with early-onset AF from the Framingham Heart Study and Massachusetts General Hospital. Specifically, we propose to: 1) Identify potentially causative genetic variants at the 9 published GWAS loci by analyzing extant targeted sequencing data of the top 5 loci for AF generated by the NIH Resequencing and Genotyping Service in 480 individuals with early-onset AF and 480 referents and by performing new targeted sequencing of 4 additional AF loci in the same subjects. 2) Replicate the top 400 AF variants with MAF>0.5% identified in our targeted sequencing projects in 5,776 independent AF cases and 9,229 referents, and replicate the rare and singleton SNPs (MAF<0.5%) in the top 3 genetic regions in 1,000 independent individuals with early-onset AF and 1,000 referents. 3) Functionally evaluate the newly identified genetic variants for AF by using cellular electrophysiology to characterize coding variation in ion channel and using a combination of zebra fish, mice, and cell-based assays to examine non-coding variants at the two most promising AF related loci. Our translational approach will facilitate a greater understanding of the molecular basis of this common and morbid arrhythmia. Identification of causative variants may enhance risk stratification, and will provide preventive and therapeutic targets for drug discovery in the broader scientific and pharmaceutical community.