Neuroimaging of the schizophrenia-associated 3q29 deletion

精神分裂症相关 3q29 缺失的神经影像学

• 批准号: 10057387
• 负责人: Longchuan Li
• 金额: $ 38.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-30 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057387
• 关键词: 22q11.2; 3q29; Address; Age; Anxiety; Behavior; Behavioral; Biological Models; Biology; Birth; Brain; Cells; Characteristics; Clinical Data; Collaborations; Coupled; DNA; Data; Data Collection; DiGeorge Syndrome; Diffusion; Dimensions; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genes; Genetic; Genetic study; Genome; Goals; Grant; Heterogeneity; Human; Individual; Infrastructure; Intellectual functioning disability; Link; Literature; Measures; Modeling; Molecular; Natural History; Nature; Neurons; Patients; Persons; Phenotype; Population; Process; Property; Recurrence; Registries; Rest; Risk; Schizophrenia; Services; Structure; Syndrome; System; United States National Institutes of Health; Variant; Work; autism spectrum disorder; base; brain volume; cognitive function; cohort; executive function; functional MRI scan; high risk; induced pluripotent stem cell; insight; neurodevelopment; neuroimaging; neuropsychiatry; scaffold; schizophrenia risk; sex; stem cell differentiation

SUMMARY 3q29 deletion syndrome is caused by a recurrent typically de novo 1.6 Mb heterozygous deletion and is associated with a range of neuropsychiatric phenotypes, including mild to moderate intellectual disability, autism, anxiety, and a 40-fold increased risk for schizophrenia. Although the 3q29 deletion is rare (~1 in 30,000 births), its high risk for neuropsychiatric phenotypes coupled with its relatively low complexity (22 genes in the deletion interval) suggest the pathophysiology may yield to interrogation. Studies of the molecular, cellular, and behavioral consequences of the deletion, in both human patients and model systems, are underway by our group and others. However, disturbances in brain structure and function are not yet articulated, and we propose to investigate them using structural, diffusion, and resting-state functional MRI. This is the first neuroimaging study of the 3q29 deletion. To accomplish our aims, we have established the Emory 3q29 Project (http://genome.emory.edu/3q29/), where the overarching goal is to understand the basis of 3q29 deletion-associated phenotypes. We have also created the 3q29 deletion registry (3q29deletion.org), where despite the low population frequency of the deletion (1 in 30,000) we have ascertained over 100 carriers (ranging in age from 1.5 – 34 years), the largest cohort ever assembled. This infrastructure, along with our existing NIH-funded grant (“Modeling the Human Neuronal Phenotype of the Schizophrenia-Associated 3q29 Deletion,” MPI Mulle/Bassell, 1 R01 MH110701), allows us to conduct in-person phenotypic assessments of 3q29 deletion patients, generating a rich set of behavioral and clinical data. This existing effort, while exciting, lacks integrated collection of data at the level of brain systems. We propose adding this additional dimension of data collection to our ongoing effort in order to identify volumetric, structural connectivity, and functional connectivity alterations that are characteristic of 3q29 deletion syndrome. We will also perform a comparison between 3q29 deletion and another variant with an extremely high risk for schizophrenia, the well-known 22q11.2 deletion. Defining the impact of the 3q29 deletion on brain systems may serve as a fundamental link bridging molecular deficits and behavioral manifestations.

概括 3Q29缺失综合征是由反复发生的，通常是从头开始1.6 MB杂合缺失 并与一系列神经精神型表型有关，包括轻度至现代 智力残疾，自闭症，动画以及精神分裂症的风险增加40倍。虽然 3Q29删除很少见（〜30,000个出生中的1个），其神经精神型表型的高风险 具有相对低的复杂性（缺失间隔中的22个基因）提示病理生理学 可能屈服于审讯。研究分子，细胞和行为后果的研究 在人类患者和模型系统中，删除都在我们的小组和其他人中进行。 但是，尚未阐明大脑结构和功能的灾难，我们建议 使用结构，扩散和静止状态功能MRI调查它们。这是第一个 3Q29缺失的神经影像学研究。为了实现我们的目标，我们已经建立了 Emory 3Q29项目（http://genome.emory.edu/3q29/），总体目标是 了解与3q​​29缺失相关表型的基础。我们还创建了3Q29 删除注册表（3Q29DELETION.org），其中目的地删除的人口低频率 （30,000分之一）我们已经确定了100多个承运人（从1.5 - 34岁不等）， 有史以来最大的队列组装。这种基础设施以及我们现有的NIH资助的赠款 （“对精神分裂症相关的3q29缺失的人类神经元表型进行建模”，MPI Mulle/Bassell，1 R01 MH110701），允许我们进行面对面的表型评估 3Q29删除患者，产生大量的行为和临床数据。这项现有的努力， 尽管令人兴奋，但缺乏大脑系统级别的数据集合。我们建议添加 数据收集的额外维度是我们正在进行的努力，以确定体积， 结构连通性和功能连接变化的特征是3q29 缺失综合征。我们还将进行3q29删除与另一个变体之间的比较 具有精神分裂症的风险极高，著名的22q11.2缺失。定义 3q29删除对脑系统的影响可能是桥接分子的基本链接 缺陷和行为表现。