GWAS TO GENE FUNCTION: NOS1AP AND OTHER QT INTERVAL GENES

GWAS 与基因功能：NOS1AP 和其他 QT 间期基因

基本信息

批准号：
9113648
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 60.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113648
关键词：
Action Potentials Adult Affinity African Alleles Architecture Arrhythmia Base Sequence Beer Binding Binding Sites Biological Assay Biological Models Cardiac Cell Culture Techniques Cell Line Chromatin Collaborations Complex Computational algorithm Computer Simulation DNA Sequence DNA-Binding Proteins Data Databases Disease EP300 gene Electrophoretic Mobility Shift Assay Electrophysiology (science)Enhancers European Evaluation Future GATA4 gene Gene Targeting Genes Genetic Genetic Polymorphism Genetic Transcription Genomics Goals Health Heart Heterogeneity High-Throughput Nucleotide Sequencing Human Hypersensitivity In Vitro Individual Infection Insulator Elements Label Laboratories Long QT Syndrome Machine Learning Maps Mass Spectrum Analysis Meta-Analysis Methods MicroRNAs Modeling Molecular Molecular Genetics Molecular Structure Muscle Cells Neonatal Nuclear Extract Oligonucleotides Phenotype Positioning Attribute Protein Microchips Proteins Quantitative Trait Loci Rattus Regulatory Element Reporter Research Resolution Risk Signal Transduction Site Tissues Transcript Untranslated RNA Validation Variant Ventricular Weight base chromatin immunoprecipitation differential expression epigenomics exome exome sequencing gene function genetic variant genome wide association study genome-wide improved in vivo knock-down novel programs promoter rare variant sudden cardiac death trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) of the electrographic QT-interval, an intermediate trait that impacts the risks of long QT syndrome and sudden cardiac death, have identified 68 independent variants at 35 loci, explaining 8% of the phenotypic (20% of the additive) variance. Nevertheless, the identity, function and mechanisms of action of the underlying DNA sequence variants and genes remain unknown, and are major impediments for understanding the molecular structure and functional architecture of this complex phenotype. We hypothesize that the majority of functional trait variants are polymorphic, non-coding and perturb transcription of a specific gene by altering the functions of their cis-regulatory elements. We propose a research paradigm for systematically identifying these non-coding trait variants, the regulatory functions they disrupt and the specific genes whose functions are altered at each quantitative trait locus. We will utilize integrative statisticl genetic, computational, molecular genetics and cellular approaches for elucidating the underlying mechanisms, using QT interval as a model 'system'. Our specific aims are: (1) to perform high- resolution mapping of GWAS signals to identify all polymorphic (>1%) and rare variants at loci that modulate the QT-interval; (2) to conduct in silico and in vitro analysis to predict and prioritize all cardiac regulatory (enhancer, silencer, insulator) elements and their cognate DNA-binding proteins; and, (3) to identify trait variants, genes and their mechanisms of genetic action. The overall goals are to improve the molecular genetic and mechanistic understanding of multifactorial traits for applications to other complex phenotypes.

描述（由申请人提供）：电描记 QT 间期（一种影响长 QT 综合征和心源性猝死风险的中间特征）的全基因组关联研究 (GWAS) 已在 35 个位点确定了 68 个独立变异，解释了 8%表型（加性的 20%）方差。然而，潜在DNA序列变体和基因的身份、功能和作用机制仍然未知，并且是理解这种复杂表型的分子结构和功能架构的主要障碍。我们假设大多数功能性状变异是多态性的、非编码的，并通过改变顺式调控元件的功能来扰乱特定基因的转录。我们提出了一种研究范式，用于系统地识别这些非编码性状变异、它们破坏的调节功能以及在每个数量性状基因座上功能发生改变的特定基因。我们将利用综合统计遗传学、计算、分子遗传学和细胞方法来阐明潜在的机制，并使用 QT 间期作为模型“系统”。我们的具体目标是：(1) 对 GWAS 信号进行高分辨率映射，以识别调节 QT 间期的基因座上的所有多态性 (>1%) 和罕见变异； (2) 进行计算机和体外分析，以预测所有心脏调节（增强子、消音器、绝缘子）元件及其同源 DNA 结合蛋白并确定优先顺序； (3) 识别性状变异、基因及其遗传作用机制。总体目标是提高对多因素性状的分子遗传学和机制理解，以应用于其他复杂表型。