Defining the functional variation underlying atrial fibrillation risk

定义心房颤动风险背后的功能变异

• 批准号: 10115201
• 负责人: Nathan Tucker
• 金额: $ 16.74万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115201
• 关键词: Address; Adult; Affect; Age; Alleles; Allelic Imbalance; American; Appointment; Arrhythmia; Atrial Fibrillation; Bioinformatics; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Cessation of life; ChIP-seq; Chromatin; Clinical; Clinical Treatment; Complex Genetic Trait; Computational Biology; Data; Dementia; Development; Disease; Enhancers; Epigenetic Process; Foundations; Gene Expression; Gene Targeting; General Hospitals; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Genotype; Goals; Graduate Education; Healthcare Systems; Heart Atrium; Heart failure; Heritability; Histones; Hospitalization; Human; In Situ Hybridization; Individual; Interdisciplinary Study; Intervention; Knowledge; Lead; Left; Left atrial structure; Link; Maps; Massachusetts; Measurement; Medicine; Mentors; Modeling; Molecular Biology; Morbidity - disease rate; Pathogenesis; Pathway interactions; Population; Post-Translational Protein Processing; Predisposition; Preventive care; Publishing; Pulmonary veins; Regulatory Element; Reporter; Research; Research Personnel; Risk; Risk Factors; Signal Transduction; Stimulus; Striated Muscles; Stroke; Tissue Banks; Universities; Untranslated RNA; Variant; Washington; Work; base; career; causal variant; clinical risk; cost; disorder risk; epigenomics; experimental study; functional genomics; gene function; genetic association; genome sequencing; genome wide association study; genomic locus; human disease; improved; insight; instructor; interest; medical schools; molecular modeling; mortality; new therapeutic target; novel therapeutic intervention; novel therapeutics; post-doctoral training; risk variant; skills; societal costs; sound; systems research; trait; transcriptome sequencing; treatment planning

Project Summary: Atrial fibrillation (AF) is the most common cardiac arrhythmia, which affects over 3 million Americans. AF confers an increased risk of hospitalization, stroke, dementia, heart failure and death and places a major burden on the healthcare system. AF, particularly in younger individuals, arises from the ectopic stimuli within the pulmonary veins with propagation to left atrium; however, many other aspects of the underlying mechanisms for AF remain unresolved. Although many clinical risk factors have been identified, in recent years we have come to appreciate that AF is heritable. A proportion of this heritability is conferred through common genetic variation. Using, genome-wide association studies (GWAS), our group and others have identified 26 independent genetic loci for AF. These loci can provide a unique and often unexpected window into the mechanisms of disease; however, as with other GWAS studies, a primary challenge is moving from an association to a specific disease mechanism. There are at least three major challenges that make it difficult to link a genetic association to a specific disease mechanism. First, GWAS loci often reside in gene-dense regions, making it difficult to identify which gene is associated with disease. Second, the overwhelming majority of GWAS loci reside in non-coding regions of the genome. The disease risk variants are presumed to alter the activity of regulatory elements that modulate nearby gene expression in a cell-specific manner. Finally, these GWAS loci can be large, and it can be challenge to identify the functional variant from among the many common variants at a locus. Given these challenges, the truly causative variants and the gene of interest are unknown for most GWAS loci. This knowledge gap greatly impedes the ability to leverage GWAS data for translational potential, as any modeling of gene function at these loci would be speculative. These issues are not exclusive to AF, instead pertaining not only to similar studies across other cardiovascular diseases and traits, but also the thousands of GWAS loci in the full spectrum of human diseases and traits uncovered in the past decade. The focus of the current proposal is to address these knowledge gaps for AF GWAS loci, with the ultimate goal of applying new insights to other cardiovascular disease loci. Given the genomic localization of most GWAS signals, this proposal operates under the overarching hypothesis that non-coding variation at AF- association loci alters gene expression in adult human left atrium, ultimately leading to AF susceptibility. We propose to leverage the genome sequencing based association data and our left atrial tissue repository for epigenetic definition and functional variant discovery. We will then use the same genotype information to identify the gene targets of each association locus.

项目概要： 心房颤动（AF）是最常见的心律失常，影响超过300万美国人。AF 导致住院、中风、痴呆、心力衰竭和死亡的风险增加， 加重了医疗系统的负担。房颤，特别是在年轻人中，是由体内的异位刺激引起的。 肺静脉与左心房的传播;然而，许多其他方面的潜在的 AF的机制尚未解决。虽然许多临床风险因素已被确定，近年来， 我们已经认识到房颤是可遗传的。 这种遗传性的一部分是通过共同的遗传变异赋予的。使用，全基因组 关联研究（GWAS），我们的小组和其他人已经确定了26个独立的遗传位点的AF。 基因座可以提供一个独特的，往往是意想不到的窗口，疾病的机制;然而， 在其他GWAS研究中，主要的挑战是从关联转移到特定的疾病机制。 至少有三个主要的挑战使得很难将遗传关联与特定的 发病机制首先，GWAS基因座通常位于基因密集区，因此难以确定哪些基因是GWAS基因座。 基因与疾病有关。其次，绝大多数GWAS基因座位于非编码区， 基因组区域。疾病风险变异被认为改变了调节元件的活性， 以细胞特异性方式调节附近的基因表达。最后，这些GWAS基因座可以很大， 从基因座上的许多常见变异中鉴定功能变异是一个挑战。 考虑到这些挑战，对于大多数GWAS来说，真正的致病变异和感兴趣的基因是未知的 的位点这种知识差距极大地阻碍了利用GWAS数据进行翻译潜力的能力， 在这些基因座上的基因功能的建模将是推测性的。这些问题并非AF独有， 不仅与其他心血管疾病和特征的类似研究有关，而且与成千上万的 在过去十年中发现的人类疾病和特征的全谱中的GWAS基因座。 当前提案的重点是解决AF GWAS基因座的这些知识缺口，最终 目的是将新的见解应用于其他心血管疾病位点。鉴于大多数的基因组定位 GWAS信号，该提议在总体假设下运作，即AF- 相关基因座改变成人左心房基因表达，最终导致房颤易感性。我们 建议利用基于基因组测序的关联数据和我们的左心房组织库， 表观遗传学定义和功能变体发现。然后，我们将使用相同的基因型信息， 确定每个关联位点的基因靶点。