Identification of Common Genetic Variants for Atrial Fibrillation and PR Interval

描述（由申请人提供）：心房颤动是最常见的心律失常。预计到2050年，它将影响600万至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、痴呆风险增加一倍、心力衰竭风险增加三倍和死亡率增加近两倍相关。估计每年因房颤造成的医疗保健额外费用接近260亿美元。房颤具有遗传性，近年来通过全基因组关联研究发现了房颤的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，并确定了AF的6个新位点。我们将在之前的工作基础上，采用多学科方法，整合所有9个AF GWAS位点的靶向测序，在CHARGE AF Consortium中进行稳健复制，以及基于模型系统的功能分析。我们将利用来自弗雷明汉心脏研究和马萨诸塞州总医院的两个特征良好的早发性房颤队列。具体而言，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（NIH Resequencing and Genotyping Service）对480例早发性房颤患者和480例参照物生成的房颤前5个位点的现有靶向测序数据，以及对同一受试者中另外4个房颤位点进行新的靶向测序，确定9个已发表的GWAS基因座的潜在致病基因变异。2)在5776例独立AF病例和9229例参照物中复制目标测序项目中鉴定的MAF >.5 %的前400个AF变异，在1000例早发AF独立个体和1000例参照物中复制前3个遗传区域的罕见单例snp （MAF<0.5%）。3)通过细胞电生理学表征离子通道编码变异，结合斑马鱼、小鼠和细胞检测两个最有希望的AF相关位点的非编码变异，对新发现的AF遗传变异进行功能评估。我们的翻译方法将有助于更好地理解这种常见和病态心律失常的分子基础。识别致病变异可能会加强风险分层，并将为更广泛的科学和药学界的药物发现提供预防和治疗靶点。

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.