Regulatory Variants of Widely-Expressed Genes and Their Role in Disease Susceptib

描述（由申请人提供）：调节变异在疾病易感性中起重要作用。全基因组关联的结果已经确定了许多与疾病相关的DNA变异。然而，这些变异如何影响疾病易感性在很大程度上是未知的。其中一些变异调节基因表达，但这些调节变异的靶基因尚未确定。一个挑战是确定相关的细胞类型/组织进行功能分析。在人体研究中，许多细胞类型不容易用于实验。因此，了解基因调控中的细胞类型特异性是很重要的。如果许多基因被广泛表达，并且它们的调控在多种细胞类型中是相似的，那么人们就可以使用现成的组织进行功能研究，并期望结果能够普遍化。在这个R21项目中，我们的目标是确定在人类基因组中广泛表达的基因的数量（和身份），以及它们的表达在不同细胞类型中共享的程度。我们还将研究广泛表达的基因的调控变异体是否是人类性状和疾病的易感性变异体。具体目标是：1)通过对公共存储库中的基因表达数据进行计算机分析和深度测序，鉴定在多种组织和条件下表达的基因；2)通过网络分析和基因定位研究，比较在不同人类细胞中表达的基因的调控；3)确定Aim 2中鉴定的调控变异是否为常见复杂疾病的易感等位基因。这些发现将指导功能性研究，以确定疾病易感性变异的调节作用。该结果还将提供影响人类基因表达水平的疾病易感性等位基因的例子。许多研究已经确定了影响一个人患疾病风险的DNA序列。重要的下一步是研究这些DNA序列如何影响疾病的发展。人体研究是困难的，因为许多细胞类型不能用于实验操作。我们的研究旨在确定调节功能是否在不同的细胞之间共享。这一结果将有助于确定血液和皮肤细胞等容易获得的细胞是否可以用作检测影响疾病风险的DNA序列的生物学功能的代理。

DESCRIPTION (provided by applicant): Regulatory variants play important roles in disease susceptibility. Results from genome-wide association have identified many DNA variants that are associated with diseases. However, how these variants influence disease susceptibility is largely unknown. Some of these variants regulate gene expression but the target genes of these regulatory variants have yet to be identified. A challenge is to decide the relevant cell types/ tissues for functional analyses. In human studies, many cell types are not readily available for experimentation. Thus, the knowledge of cell type specificities in gene regulation is important. If many genes are widely expressed and their regulations are similar across multiple cell types, then one can use readily available tissues for functional studies, and expect the results to generalize. In this R21 project, our goal is to determine the number (and identity) of genes that are widely expressed in the human genome, and the extent to which their expression is shared across cell types. We will also examine whether regulatory variants of widely expressed genes are susceptibility variants for human traits and diseases. The specific aims are: 1) identify genes that are expressed across multiple tissues and conditions by in silico analysis of gene expression data in public repositories and deep sequencing, 2) compare regulation of genes that are expressed across different human cells by network analysis and gene mapping studies, and 3) determine whether regulatory variants identified in Aim 2 are susceptibility alleles for common complex diseases. The findings will guide functional studies to identify the regulatory roles of disease susceptibility variants. The results will also provide examples of disease susceptibility alleles that influence expression levels of human genes. Numerous studies have identified DNA sequences that influence a person's risk of developing diseases. An important next step is to study how these DNA sequences affect disease development. Human studies are difficult because many cell types are not available for experimental manipulations. Our study is designed to establish whether regulatory functions are shared among different cells. The results will help to determine whether easily accessible cells such as blood and skin cells can be used as proxies to examine the biological functions of DNA sequences that influence disease risks.