Understanding the Genetic Architecture of Gene Expression Regulation

了解基因表达调控的遗传结构

• 批准号: 8060613
• 负责人: ALKES L PRICE
• 金额: $ 8.18万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060613
• 关键词: Adipose tissue; Admixture; Affect; African; African American; Animal Model; Architecture; Blood; Categories; Chromosomes; Chromosomes, Human, Pair 2; Collaborations; Data; Data Analyses; European; Family; Family Study; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Code; Genetic Variation; Genome; Genotype; Heritability; Histocompatibility Testing; Human; Individual; Inherited; Lead; Letters; Light; Location; Measurement; Methods; Modeling; Mus; Phenotype; Population; Regulation; Relative (related person); Research; Tissues; Variant; cohort; disorder risk; family structure; genetic pedigree; genome wide association study; public health relevance; success; trait

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.

描述（由申请人提供）：基因表达是人类和模型生物体表型变异的基本决定因素。已知基因表达的调节具有重要的遗传成分，并且被认为是对疾病风险和其他表型变异的大部分遗传贡献的基础。因此，为了了解遗传变异如何影响表型变异，了解遗传变异如何影响基因表达水平非常重要。尽管之前的研究已经确定了个体调控变异，但对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包括个体顺式变体、个体反式变体以及多个顺式和/或反式变体网络之间的上位相互作用。在本提案中，我们将应用群体混合、家族结构和模式生物方法来了解这些组成部分对遗传性的贡献。我们还将得出关于长程顺式效应、顺式-顺式相互作用以及跨组织类型的共享遗传调控的结论。由于检测不同效应的能力存在巨大差异，我们提出的方法比计算这些类别中可靠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公正结论。我们的研究将有助于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基因的开启和关闭，并被广泛认为可以解释遗传对疾病风险的大部分影响。基因表达调控可能受到靠近被打开和关闭的基因的基因组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。在本提案中，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。

项目成果

Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals.

通过相关或不相关个体的血统同一性来实现基因表达的单组织和跨组织遗传力。

• 发表时间: 2011-02
• 影响因子: 4.5
• 作者: Price, Alkes L;Helgason, Agnar;Thorleifsson, Gudmar;McCarroll, Steven A;Kong, Augustine;Stefansson, Kari
• 通讯作者: Stefansson, Kari