Mapping functional brain connectivity, neurodevelopment, and imaging-genetic associations in individuals with genetic and clinical risk factors for neuropsychiatric illness

项目总结 在精神分裂症(SCZ)等神经发育障碍中，遗传和环境因素汇聚在一起 大脑发育和功能受阻。有一种方法可以让我们更清楚地了解 基因、神经系统和症状是通过考虑对大脑有较大影响的罕见遗传疾病来实现的 发展。22q11.2缺失综合征(22qDel)是一种反复发生的拷贝数变异(CNV)，其中 22号染色体~2.6Mb遗传物质(~46个蛋白质编码基因)的半合子缺失导致 神经发育表型有约25%的精神疾病风险和自闭症、智力障碍的发生率增加 残疾、注意力缺陷和焦虑症。因此，研究具有22qDel的个体可以提供一种 理解复杂生物途径的有效翻译模型和“遗传学优先”框架 潜在的禁用条件，如SCZ。拟议的研究计划试图绘制出趋同和发散的地图 22qDel和临床高危人群发展为精神病的脑连接障碍 与典型发育期(TD)对照相关的谱系障碍。为此，我们将利用最大的 到目前为止从22qDel(n=217)和匹配的对照组采集的纵向静息状态fMRI的多点样本 (n=149)，以及来自北美前驱症状纵向研究(NAPLS)的数据(n=318)和 TD(n=206)。我们还将使用艾伦人脑图谱(AHBA)的空间转录数据来测试 脑内基因表达的典型空间模式与功能磁共振生物标志物之间的关系。具体来说， 我们的目标是：(I)测试这一假设，即遗传性和非遗传性疾病患者的功能连接中断 精神病的临床风险因素集中在全脑的感觉和执行网络上，(Ii)检验这一假设 22qDel和CHR将在整个年龄段的功能连接发展中表现出汇聚性中断 相对于TD控制的范围，个体偏离典型轨迹将预测精神病 症状，以及(Iii)测试22qDel静息状态fMRI中断的空间模式的假设 死后脑组织抑制性和兴奋性神经元基因表达的空间梯度关系 从典型的成年人身上。这种多模式方法旨在阐明脑生物标记物和神经生物学 与精神病谱系障碍的遗传和临床危险因素相关的机制。为了促进这一点 研究，拟议的培训计划包括课程作业、研讨会和职业发展活动 与多点数据分析、纵向数据分析、神经遗传学和科学传播相关。这个 加州大学洛杉矶分校的比尔登实验室和神经科学跨部门项目将 为拟议的培训和研究计划提供理想的学术环境。

PROJECT SUMMARY In neurodevelopmental disorders such as schizophrenia (SCZ), genetic and environmental factors converge on disrupted brain development and function. One way that we can gain more clarity on the relationships between genes, neural systems, and symptoms is through considering rare genetic conditions with large effects on brain development. 22q11.2 Deletion Syndrome (22qDel) is a recurrent copy number variant (CNV) in which a hemizygous deletion of ~2.6 Mb of genetic material (~46 protein-coding genes) from chromosome 22 causes a neurodevelopmental phenotype with a ~25% risk of psychotic illness and increased rates of ASD, intellectual disability, attention deficit and anxiety disorders. Studying individuals with 22qDel can therefore provide an impactful translational model and ‘genetics-first’ framework for understanding the complex biological pathways underlying disabling conditions like SCZ. The proposed research plan seeks to map convergent and divergent brain connectivity disruptions in 22qDel and in individuals at Clinical High Risk (CHR) for developing psychosis spectrum disorders relative to typically developing (TD) controls. To this end, we will make use of the largest multi-site sample collected to date of longitudinal resting-state fMRI from 22qDel (n=217) and matched controls (n=149), along with data from the North American Prodrome Longitudinal Study (NAPLS) with CHR (n=318) and TD (n=206). We will also apply spatial transcriptomic data from the Allen Human Brain Atlas (AHBA) to test relationships between fMRI biomarkers and typical spatial patterns of gene expression in the brain. Specifically, our aims are to: (i) Test the hypothesis that functional connectivity disruptions in individuals with genetic and clinical risk factors for psychosis converge on brain-wide sensory and executive networks, (ii) Test the hypothesis that 22qDel and CHR will exhibit convergent disruptions in functional connectivity development across the age range relative to TD controls, and that individual deviations from typical trajectories will predict psychosis symptoms, and (iii) Test the hypothesis that spatial patterns of resting-state fMRI disruptions in 22qDel are related to spatial gradients of inhibitory and excitatory neuronal gene expression in post-mortem brain tissue from typical adults. This multimodal approach aims to elucidate brain biomarkers and neurobiological mechanisms related to genetic and clinical risk factors for psychosis spectrum disorders. To facilitate this research, the proposed training plan includes coursework, workshops, and professional development activities related to analysis of multi-site data, longitudinal data analysis, neurogenetics, and science communication. The Bearden Lab and Neuroscience Interdepartmental Program at the University of California Los Angeles will provide the ideal academic environment for the proposed training and research plan.