The influence of common genetic variation on brain overgrowth pathways

常见遗传变异对大脑过度生长途径的影响

• 批准号: 10407571
• 负责人: Jason Louis Stein
• 金额: $ 40.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407571
• 关键词: Adult; Affect; Area; Behavioral; Biological; Biological Assay; Brain; Cell Line; Cells; Clinical; Code; Data; Development; Developmental Process; Disease; Dose; Environmental Risk Factor; Exhibits; Exposure to; Fetal Development; Fetal Tissues; Flow Cytometry; Gene Expression; Genes; Genetic Transcription; Genetic Variation; Genotype; Goals; Human; Individual; Lead; Libraries; Life; Link; Lithium Chloride; Luciferases; Measurement; Measures; Molecular; Mus; Mutation; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Population; Process; RNA Splicing; Reporter; Research; Risk; Role; Signal Transduction; Structure; Surface; Techniques; Time; Valproic Acid; Variant; WNT Signaling Pathway; Work; autism spectrum disorder; base; beta catenin; brain overgrowth; brain volume; cell type; clinically relevant; design; differential expression; disorder risk; fetal; genetic association; genetic risk factor; genetic variant; genome wide association study; in vitro Model; induced pluripotent stem cell; inter-individual variation; molecular phenotype; neocortical; nerve stem cell; neurodevelopmental effect; pleiotropism; prenatal exposure; progenitor; rare variant; relating to nervous system; response; risk variant; transcriptome sequencing

Project Summary Many individuals with monogenic and idiopathic forms of autism spectrum disorder (ASD) exhibit larger brain volumes and a hyper-expansion of neocortical surface area early in life. An increase in the neural progenitor pool, present almost exclusively during fetal development, is a well-described mechanism that can lead to expansion of neocortical surface area. Numerous ASD-linked mutations affect genes involved in Wnt signaling, a pathway that regulates neural progenitor proliferation. In addition, common genetic variants near Wnt- pathway genes are associated with changes in cortical surface area in adults. Common variation plays a large role in ASD risk. Large and ever-growing genome-wide association consortia are identifying common variant loci associated with ASD risk. Based on these data, we hypothesize that both common and rare variants impact neocortical progenitor proliferation in fetal development by altering Wnt signaling, leading to post-natal cortical surface area hyper-expansion and increased ASD risk. The primary goal of this project is to identify common genetic variants influencing gene expression, Wnt signaling, and proliferation in response to Wnt modulators in primary human neuronal progenitor cell lines (phNPCs) from 107 genetically diverse donors. To accomplish this goal, we will first quantify inter-individual variability in transcriptional response to Wnt modulators. To modulate Wnt signaling, we will utilize two clinically relevant compounds (Valproic Acid, Lithium Chloride) as well as the most potent and selective Wnt activating compound available (CT99021). Next, we will quantify both canonical Wnt signaling, through a high-throughput luciferase assay, and proliferation, through a flow cytometry assay, in response to these Wnt modulators in this population of cells. Finally, we will perform a genetic association using the phenotypes we have collected on these cell lines to identify common variant loci associated with transcriptional, Wnt signaling and neural progenitor proliferation responses to Wnt modulators. We will determine if these same loci also influence risk for ASD and cortical surface area through co- localization techniques using existing genome-wide association studies. This study may allow us to understand the mechanism of action of ASD-associated genetic variation, implicating a cell-type and developmental process, which may lead to a more thorough understanding of ASD pathogenesis. In addition, as prenatal exposure to Valproic Acid is a known environmental risk factor for ASD, this study may identify genetic variants that impact responsiveness to Valproic Acid, allowing the prediction of adverse neurodevelopmental effects based on genotype.

项目摘要 许多具有自闭症谱系障碍（ASD）的单基因和特发性形式的人表现出更大的大脑 生命早期，新皮质表面积的体积和过度扩张。神经祖细胞的增加 池几乎完全存在于胎儿发育期间，是一种描述良好的机制，可以导致 新皮质表面积的扩展。许多ASD连接的突变会影响与Wnt信号传导有关的基因， 调节神经祖细胞增殖的途径。另外，Wnt-附近的常见遗传变异 途径基因与成人皮质表面积的变化有关。普通变化很大 在ASD风险中的作用。大型且不断增长的全基因组关联联盟正在识别常见变体 与ASD风险相关的基因座。基于这些数据，我们假设常见和稀有变体 通过改变Wnt信号传导，影响新皮层祖细胞增殖在胎儿发育中，导致产后 皮质表面积超扩张和增加的ASD风险。该项目的主要目标是确定 常见的遗传变异会影响基因表达，Wnt信号传导和增殖，以响应Wnt 来自107个遗传供体的原代人神经祖细胞系（PHNPC）中的调节剂。到 实现这一目标，我们将首先量化对Wnt的转录响应中个体间的可变性 调节器。为了调节Wnt信号，我们将使用两种临床相关化合物（丙戊酸，锂 氯化物）以及最有效，最有选择的Wnt激活化合物（CT99021）。接下来，我们会的 通过高通量荧光素酶测定和增殖，量化两种规范的Wnt信号传导 流式细胞仪测定法对这些细胞群中的这些WNT调节剂的响应。最后，我们将执行 使用我们在这些细胞系上收集的表型的遗传关联以识别常见的变异基因座 与转录，WNT信号传导和神经祖细胞增殖对Wnt调节剂的反应相关。 我们将确定这些基因座是否也会通过共同影响ASD和皮质表面积的风险 使用现有全基因组关联研究的定位技术。这项研究可能使我们能够理解 与ASD相关的遗传变异的作用机理，暗示细胞类型和发育 过程，这可能会导致对ASD发病机理的更彻底的了解。另外，作为产前 接触丙戊酸是ASD的已知环境风险因素，这项研究可能鉴定遗传变异 这会影响对丙戊酸的反应性，从而预测不良神经发育效应 基于基因型。