Understanding the Genetic Architecture of Gene Expression Regulation

描述（由申请人提供）：基因表达是人类和模式生物中表型变异的基本决定因素。基因表达的调控被认为具有相当大的遗传成分，并且被认为是疾病风险和其他表型变异的遗传贡献的基础。因此，为了了解遗传变异如何影响表型变异，重要的是要了解遗传变异如何影响基因表达水平。虽然以前的研究已经确定了个别的调控变异，基因表达调控的整体遗传结构知之甚少。基因表达的遗传控制可以包括单独的顺式变体、单独的反式变体以及多个顺式和/或反式变体的网络之间的上位相互作用。在这个建议中，我们将应用人口混合，家庭结构和模式生物的方法来了解这些组成部分的遗传遗传力的贡献。我们还将得出结论的长期顺式效应，顺式-顺式相互作用，跨组织类型的共享遗传调控。由于检测不同效应的能力存在很大差异，我们提出的方法比计算这些类别中稳健识别的关联数量的方法更有可能得出关于基因表达的遗传结构的无偏结论。我们的研究将使人们更好地了解遗传变异如何影响基因表达和疾病风险。 公共卫生相关性：基因表达调控是指我们的遗传密码如何影响哪些基因被打开和关闭，并被广泛认为可以解释许多遗传因素对疾病风险的影响。基因表达调控可能受到基因组中接近基因开启和关闭的部分的遗传变异的影响，或者受到基因组其他部分的遗传变异的影响，或者受到这些效应的组合的影响。在这项提案中，我们将分析来自多个人群和家庭队列的数据，以了解这些因素如何影响基因表达。

DESCRIPTION (provided by applicant): Gene expression is a fundamental determinant of phenotypic variation in humans and model organisms. Regulation of gene expression is known to have a substantial heritable component, and is believed to underly much of the genetic contribution to disease risk and other phenotypic variation. Thus, in order to understand how genetic variation affects phenotypic variation, it is important to understand how genetic variation affects gene expression levels. Although previous studies have identified individual regulatory variants, the overall genetic architecture of gene expression regulation is poorly understood. Genetic control of gene expression may include individual cis variants, individual trans variants, as well as epistatic interactions between networks of multiple cis and/or trans variants. In this proposal, we will apply population admixture, family structure and model organism approaches to understanding the contributions of these components to genetic heritability. We will also draw conclusions about long-range cis effects, cis-cis interactions, and shared genetic regulation across tissue types. Due to large differences in power to detect different effects, the approaches we propose have a greater chance of yielding unbiased conclusions about the genetic architecture of gene expression than the approach of counting the number of robustly identified associations in these categories. Our research will lead to a greater understanding of how genetic variation affects gene expression and disease risk. PUBLIC HEALTH RELEVANCE: Gene expression regulation refers to how our genetic code affects which genes are turned on and off, and is widely believed to explain much of the genetic contribution to disease risk. Gene expression regulation may be affected by genetic variation in the part of the genome close to the gene being turned on and off, or by genetic variation in other parts of the genome, or by combinations of these effects. In this proposal, we will analyze data from multiple populations and family cohorts to understand how these factors influence gene expression.