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

绘制具有神经精神疾病遗传和临床危险因素的个体的功能性大脑连接、神经发育和成像-遗传关联

• 批准号: 10678553
• 负责人: Charles Schleifer
• 金额: $ 3.97万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678553
• 关键词: Adolescence; Adult; Age; American; Anxiety Disorders; Atlases; Attentional deficit; Autopsy; Behavior; Behavioral; Biological; Biological Markers; Brain; Brain region; California; Chromosome 22; Clinical; Code; Communication; Complex; Copy Number Polymorphism; Data; Data Analyses; Data Set; Development; DiGeorge Syndrome; Diagnosis; Disease; Educational workshop; Environment; Environmental Risk Factor; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Diseases; Genetic Materials; Genetic Risk; Heritability; Hippocampus; Human; Individual; Intellectual functioning disability; Interneurons; Location; Longitudinal Studies; Los Angeles; Magnetic Resonance Imaging; Maps; Measures; Micro Array Data; Modeling; Neurodevelopmental Disorder; Neurons; Neurosciences; Parvalbumins; Pathway interactions; Patients; Pattern; Phenotype; Population; Proteins; Psychoses; Psychotic Disorders; Recurrence; Research; Rest; Risk; Risk Factors; Sampling; Schizophrenia; Science; Sensory; Severities; Signal Transduction; Site; Symptoms; Syndrome; System; Testing; Thalamic structure; Tissues; Training; Universities; Work; Youth; age related; autism spectrum disorder; blood oxygen level dependent; brain based; brain tissue; cell type; clinical high risk for psychosis; clinical risk; cohort; excitatory neuron; follow-up; genetic association; genetic risk factor; high risk; hippocampal pyramidal neuron; imaging genetics; indexing; inhibitory neuron; longitudinal dataset; mouse model; multimodality; neural; neurobiological mechanism; neurodevelopment; neurogenetics; neuroimaging; neuronal patterning; neuropsychiatric disorder; neuropsychiatry; programs; psychosis risk; tool; transcriptomics; translational model; young adult

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.

项目概要 在精神分裂症 (SCZ) 等神经发育障碍中，遗传因素和环境因素共同作用 我们可以更清楚地了解大脑发育和功能之间的关系的一种方法。 基因、神经系统和症状是通过考虑对大脑有重大影响的罕见遗传条件 22q11.2 缺失综合征 (22qDel) 是一种复发性拷贝数变异 (CNV)，其中 从 22 号染色体上半合子删除约 2.6 Mb 的遗传物质（约 46 个蛋白质编码基因）会导致 神经发育表型，患精神病的风险约为 25%，自闭症谱系障碍（ASD）、智力障碍的发生率增加 因此，研究 22qDel 患者可以提供关于残疾、注意力缺陷和焦虑症的信息。 有影响力的转化模型和“遗传学优先”框架，用于理解复杂的生物途径 拟议的研究计划旨在绘制趋同和趋异的情况。 22qDel 和患有精神病的临床高风险 (CHR) 个体的大脑连接中断 相对于典型发育（TD）对照的谱系障碍为此，我们将利用最大的。 迄今为止从 22qDel (n=217) 和匹配对照中收集的纵向静息态 fMRI 多部位样本 (n=149)，以及来自 CHR 的北美前驱症状纵向研究 (NAPLS) 的数据 (n=318) 和 TD (n=206) 我们还将应用艾伦人脑图谱 (AHBA) 的空间转录组数据进行测试。 功能磁共振成像生物标志物与大脑中基因表达的典型空间模式之间的关系。 我们的目标是： (i) 检验以下假设：具有遗传性和遗传性的个体的功能连接中断 精神病的临床危险因素集中在全脑感觉和执行网络上，(ii) 检验假设 22qDel 和 CHR 将在整个时代的功能连接发展中表现出融合性破坏 相对于 TD 对照的范围，个体偏离典型轨迹将预测精神病 (iii) 检验以下假设：22qDel 中静息态 fMRI 中断的空间模式是 与死后脑组织中抑制性和兴奋性神经元基因表达的空间梯度有关 这种多模式方法旨在阐明大脑生物标志物和神经生物学。 与精神病谱系障碍的遗传和临床危险因素相关的机制以促进这一点。 研究，拟议的培训计划包括课程作业、研讨会和专业发展活动 与多站点数据分析、纵向数据分析、神经遗传学和科学传播相关。 加州大学洛杉矶分校比尔登实验室和神经科学跨系项目将 为拟议的培训和研究计划提供理想的学术环境。