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：
9671234
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 45.97万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9671234
关键词：
GWAS Gene Function NOS1AP Other

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）：电视QT间隔的全基因组关联研究（GWAS），这是一种影响长QT综合征和猝死的风险的中间性状，已经确定了35个基因座的68个独立变体，解释了8％的表型（20％添加剂）差异。然而，基本DNA序列变体和基因的作用的身份，功能和机制仍然未知，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体是通过改变其顺式调节元件的功能来改变特定基因的多态性，非编码和扰动转录。我们提出了一个研究范式，用于系统地识别这些非编码性状变体，它们破坏的调节函数以及在每个定量性状基因座上都会改变功能的特定基因。我们将利用QT间隔作为模型“系统”来利用统计统计遗传，计算，分子遗传学和细胞方法来阐明基本机制。我们的具体目的是：（1）执行GWAS信号的高分辨率映射，以识别调节QT间隙的所有多态性（> 1％）和基因座的稀有变体；（2）在计算机和体外分析中进行进行预测和确定所有心脏调节（增强剂，消音器，绝缘子）元素及其同源DNA结合蛋白；（3）确定性状变异，基因及其遗传作用机制。总体目标是改善对其他复杂表型应用多因素性状的分子遗传和机械理解。