Identification of common genetic variants for atrial fibrillation and PR interval

描述（由申请人提供）：房颤（AF）增加中风、心力衰竭、痴呆和死亡的风险。房颤的患病率每增加10岁就会增加一倍，多个数据来源表明，房颤的患病率随着时间的推移而增加。据估计，美国AF患病率将从2001年的230万上升到2050年的约600万至1200万。房颤的危险因素是多因素的，包括众所周知的高血压和心力衰竭，以及不太熟悉的特征，如P波形态和PR间期。传统上，基因对房颤的影响被认为是罕见的，但在过去的五年中，越来越多的数据表明，所有形式的房颤，特别是单发房颤，都是可遗传的。虽然在房颤家族和个体中发现了一系列离子通道的突变，但这些变异是该病的罕见病因。因此，房颤的遗传基础仍然是重要的，但至今仍无法解释。人类基因组和HapMap计划的出现以及高通量基因分型从根本上加速了发现人类疾病常见变异的遗传贡献的能力。全基因组关联研究（GWAS）已经发现了常见的单核苷酸多态性（snp）是糖尿病和冠心病等疾病的潜在风险，最近还发现了房颤，以及QT间期等定量表型。因此，了解共同遗传变异在房颤中的作用是至关重要的，并且最近已经实现。我们假设普通人群中常见的变异导致了房颤风险和PR间期的变化。具体目标是：目标1。使用MGH、Framingham心脏研究（FHS）、鹿特丹和心血管健康研究（CHS）对GWAS进行荟萃分析，以确定易患房颤的常见变异。目标2。在FHS、鹿特丹、CHS、MONICA/KORA和古登堡心脏（GHS）研究中对GWAS与房颤定量中间表型PR间期进行meta分析。目标3。在另外6个队列中重复前250个AF snp和前100个PR间隔snp。目标4。研究细胞和斑马鱼模型系统中Aim 3中snp复制的机制。目标5。探讨基因-环境（GEI）和基因-基因（上位性）相互作用。总之，房颤是人群发病率和死亡率的主要来源。我们汇集了一个多机构、多国家的团队，在房颤、遗传流行病学、统计遗传学、细胞电生理学和发育生物学方面具有专业知识。我们建议利用现有的队列和六个正在进行的GWAS来揭示社区中AF和PR间隔的遗传贡献。该项目的多学科广度将使GWAS的发现转化为对房颤细胞机制的基本见解。鉴定房颤涉及的基因和途径将为进一步了解房颤的发病机制提供机会，并为风险分层和未来治疗提供新的靶点。心房颤动是一种常见的不规则心律，可增加中风和死亡的风险。虽然已知房颤可以遗传，但导致房颤的具体遗传因素在很大程度上是未知的。来自弗雷明汉心脏研究、马萨诸塞州总医院、鹿特丹、心血管健康研究和范德比尔特的研究人员建议检查大型遗传筛查研究的结果，并测试美国和欧洲其他研究中最重要的发现，以发现导致房颤风险的遗传因素。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) increases the risk of stroke, heart failure, dementia and death. The prevalence of AF doubles for each advancing decade of life and multiple data sources suggest that the prevalence of AF is increasing over time. It is estimated that the U.S. prevalence of AF will rise from 2.3 million in 2001 to about 6 to 12 million in 2050. The risk factors for AF are multi-factorial, and include well-known conditions such hypertension and heart failure as well as less familiar traits such as P wave morphology and PR interval. Traditionally, genetic contributions to AF have been considered rare, but in the past five years there have been increasing data demonstrating that all forms of AF, and particularly lone AF, are heritable. Although mutations have been identified in a series of ion channels in families and individuals with AF, these variants are rare causes of the disease. Thus, there remains a significant, but as yet, unexplained genetic basis for AF. The advent of the human genome and HapMap projects and high-throughput genotyping has fundamentally accelerated the ability to discover the genetic contribution to common variation in human disease. Genome-wide association studies (GWAS) have uncovered common single nucleotide polymorphisms (SNPs) underlying risk for diseases such as diabetes and coronary heart disease, and recently AF, as well as quantitative phenotypes such as QT interval. Hence, understanding the role of common genetic variation in AF is of paramount importance and recently achievable. We hypothesize that common variants contribute to variability in AF risk and PR interval in the general population. The specific aims are: Aim 1. To perform a meta-analysis of GWAS to identify common variants predisposing to AF using MGH, Framingham Heart Study (FHS), Rotterdam and Cardiovascular Health Study (CHS). Aim 2. To conduct a meta-analysis of GWAS with PR interval, a quantitative intermediate phenotype for AF, in the FHS, Rotterdam, CHS, MONICA/KORA and Gutenberg Heart (GHS) Studies. Aim 3. To replicate the top 250 AF SNPs and top 100 PR interval SNPs in six additional cohorts. Aim 4. To study mechanisms of SNPs replicated in Aim 3 in cellular and zebrafish model systems. Aim 5. To examine gene-environment (GEI) and gene-gene (epistasis) interactions. In summary, AF is a major source of morbidity and mortality in the population. We bring together a multi- institutional, multi-national team with expertise in AF, genetic epidemiology, statistical genetics, cellular electrophysiology and developmental biology. We propose leveraging existing cohorts and six ongoing GWAS to uncover the genetic contribution to AF and PR interval in the community. The multi-disciplinary breadth of the project will allow translation of the GWAS findings into basic insights of the cellular mechanisms underlying AF. Identification of genes and pathways involved in AF will provide opportunities to advance knowledge of the pathogenesis of AF, and provide novel targets for risk stratification and future therapies. PUBLIC HEALTH RELEVANCE Atrial fibrillation, a common, irregular heart rhythm, increases the risk of stroke and death. Although it is known that atrial fibrillation can be inherited, the specific genetic factors contributing to atrial fibrillation are largely unknown. Investigators from the Framingham Heart Study, Massachusetts General Hospital, Rotterdam, Cardiovascular Health Study and Vanderbilt propose to examine the results of large genetic screening studies, and test the most important findings in other studies in the United States and Europe in order to discover genetic factors contributing to risk of atrial fibrillation.