Functional Characterization of the Genetic and Environmental Determinants of Comp

比较的遗传和环境决定因素的功能特征

• 批准号: 8887352
• 负责人: Francesca Luca
• 金额: $ 27.64万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887352
• 关键词: Affect; Alleles; Atherosclerosis; Bioinformatics; Cardiovascular Diseases; Cataloging; Catalogs; Cell Culture Techniques; Complex; Data; Environment; Environmental Exposure; Environmental Risk Factor; Gene Expression; Genetic; Genome; Genotype; Glucocorticoids; Health; Hormonal; Human; In Vitro; Individual; Libraries; Link; Linkage Disequilibrium; Maps; Methods; Modeling; Molecular; National Human Genome Research Institute; Nucleotides; Online Systems; Pathway interactions; Phase; Phenotype; Preparation; Protocols documentation; Proxy; Public Health; Reading; Risk Factors; Sampling; Series; Source; Stress; System; Tissues; Untranslated RNA; Variant; Vascular Endothelium; Work; base; cell type; computerized tools; cost; database of Genotypes and Phenotypes; epigenome; falls; follow-up; functional genomics; gene environment interaction; genetic association; genetic variant; genome wide association study; novel; research study; response; sound; tool; trait; transcriptome sequencing

DESCRIPTION (provided by applicant): Functional variants associated with complex traits tend to fall in non-coding regions and affect regulatory mechanisms that are not yet well characterized. Furthermore, it is generally difficult to determine in which tissues and conditions they may have a functional impact. This is because the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by "environmental" factors. We denominate such variants "gene-expression environment-specific quantitative trait nucleotides" GxE-QTNs. Achieving a better understanding of the mechanisms underlying GxE-QTNs is a critical step in understanding the link between genotype and complex phenotype. It is also crucial to develop computationally efficient and statistically sound methods capable to integrate tissue/condition-specific functional genomics data to predict and validate when a sequence variant is functional. We propose to develop novel experimental and computational approaches to screen, analyze and functionally characterize genetic variants for complex traits modulated by environmental exposures. To identify and characterize GxE-QTNs, we will analyze allele specific gene expression in a panel of relevant tissues (e.g. the vascular endothelium for cardiovascular diseases) under a series of controlled environmental conditions (e.g. glucocorticoids treatment, as a proxy for stress exposure). The proposed computational tools will integrate different sources of evidence including data collected by ENCODE, Road Map Epigenome and GTEx projects to functionally annotate GWAS variants. The experimental and computational tools developed by this project have widespread applicability; for example, can be used to tackle the functional basis of complex traits in other environmental contexts (e.g. other types of stress and hormonal levels) and genetic backgrounds. Relevance to public health: Our findings will represent the first comprehensive catalog of genetic variants that interact with environmental exposure in determining human complex traits.

描述（由申请人提供）：与复杂性状相关的功能变体往往位于非编码区，并影响尚未充分表征的调控机制。此外，通常难以确定它们在哪些组织和条件下可能具有功能性影响。这是因为遗传变异对分子途径的影响，并最终对个体的表型，可能会受到“环境”因素的调节。我们将这种变体命名为“基因表达环境特异性数量性状核苷酸”GxE-QTN。更好地理解GxE-QTN的机制是理解基因型和复杂表型之间联系的关键一步。它也是至关重要的，以开发计算效率和统计上健全的方法，能够整合组织/条件特异性功能基因组学数据，以预测和验证时，序列变异是功能性的。我们建议开发新的实验和计算方法来筛选，分析和功能表征遗传变异的复杂性状调制的环境暴露。为了鉴定和表征GxE-QTN，我们将在一系列受控环境条件下（例如糖皮质激素治疗，作为应激暴露的替代）分析一组相关组织（例如心血管疾病的血管内皮）中的等位基因特异性基因表达。拟议的计算工具将整合不同的证据来源，包括ENCODE，路线图表观基因组和GTEx项目收集的数据，以功能性地注释GWAS变体。该项目开发的实验和计算工具具有广泛的适用性;例如，可用于解决其他环境背景（例如其他类型的压力和激素水平）和遗传背景中复杂性状的功能基础。与公共卫生的相关性：我们的研究结果将代表第一个全面的遗传变异目录，这些遗传变异与环境暴露相互作用，以确定人类复杂的特征。