Functional Characterization of the Genetic and Environmental Determinants of Comp

描述（由申请人提供）：与复杂性状相关的功能变异往往落在非编码区，并影响尚未很好表征的调控机制。此外，通常很难确定它们在哪些组织和条件下可能具有功能影响。这是因为基因变异对分子途径的影响，以及最终对个体表型的影响，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-QTNs。更好地理解GxE-QTNs的机制是理解基因型和复杂表型之间联系的关键一步。开发计算效率高、统计可靠的方法也至关重要，这些方法能够整合组织/条件特异性功能基因组学数据，以预测和验证序列变异何时具有功能。我们建议开发新的实验和计算方法来筛选，分析和功能表征受环境暴露调节的复杂性状的遗传变异。为了鉴定和表征GxE-QTNs，我们将在一系列受控环境条件下（例如糖皮质激素治疗，作为应激暴露的代理）分析一组相关组织（例如心血管疾病的血管内皮）中等位基因特异性基因的表达。所提出的计算工具将整合不同来源的证据，包括ENCODE、Road Map表观基因组和GTEx项目收集的数据，以对GWAS变体进行功能注释。本课题开发的实验和计算工具具有广泛的适用性；例如，可以用来解决复杂性状在其他环境背景（例如其他类型的压力和激素水平）和遗传背景下的功能基础。与公共卫生的相关性：我们的发现将代表第一个全面的遗传变异目录，这些变异与环境暴露相互作用，决定了人类的复杂特征。

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.