Combined brain and gene network approaches to the developmental hypothesis of schizophrenia

大脑和基因网络相结合的精神分裂症发育假说

• 批准号: 10640119
• 负责人: Aaron Felix Alexander-Bloch
• 金额: $ 14.71万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640119
• 关键词: Acceleration; Address; Adolescence; Adolescent; Adult; Affect; Age; Anatomy; Area; Autopsy; Big Data; Bioinformatics; Biological; Biological Markers; Brain; Brain imaging; Brain region; Candidate Disease Gene; Chronic; Clinical; Clinical Data; Communities; Community Networks; Complex; Data; Data Analyses; Data Analytics; Data Set; Development; Disease; Environmental Risk Factor; Epidemiology; Faculty; Freedom; Functional Magnetic Resonance Imaging; Gene Combinations; Gene Expression; Genes; Genetic; Genomic approach; Genomics; Goals; Heritability; Human; Image; Investigation; Leukocytes; Link; Magnetic Resonance Imaging; Mediating; Mental disorders; Mentors; Mentorship; Molecular; National Institute of Mental Health; Nature; Network-based; Pathogenesis; Pathogenicity; Pathology; Pathway Analysis; Pattern; Personality; Phenotype; Process; Proteins; Psychiatry; Psychoses; Psychotic Disorders; Public Domains; Questionnaires; Research; Research Methodology; Research Personnel; Risk; Sampling; Schizophrenia; Schizotypal Personality Disorder; Science; Signal Transduction; Source; Symptoms; Synapses; Techniques; Testing; Thick; Training; Translating; Variant; Work; age effect; biotypes; brain based; brain magnetic resonance imaging; brain tissue; career; clinical phenotype; clinical risk; computerized tools; data integration; developmental disease; experience; functional disability; gene network; genetic variant; genome wide association study; genome-wide analysis; in vivo; insight; member; neurodevelopment; neuroimaging; neuropathology; novel; peripheral blood; phenomics; psychiatric genomics; psychosis risk; psychotic; risk variant; schizophrenia risk; segregation; synaptic pruning; theories; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT As a computational psychiatry faculty candidate with a strong background in neuroimaging and quantitative data analysis, I seek mentored-support to incorporate genetic and transcriptomic data into my work during my path towards independence as an investigator. I propose a project at the intersection of human neuroimaging, genomics and transcriptomics, using computational tools from network theory to investigate risk for schizophrenia and other forms of chronic psychosis. Prior work suggests that synaptic over-pruning in adolescence disrupts functional and structural connectivity within brain networks, giving rise to symptoms and functional impairments associated with schizophrenia. This process is a product of the interplay of genetic and environmental factors in development, and it is reflected in alterations observed in structural and functional neuroimaging. Network-based analytic approaches allow one to extract deeper insights into the nature of the disturbances in network function, in contrast to simpler attempts to link complex diseases to single brain regions, genes or proteins. The project uses an imaging-genomics approach to test whether networks of genes that are implicated in schizophrenia risk by genome-wide studies of common genetic variants – and have been shown in many cases to be related to synaptic integrity – affect the development of cortical thickness and the functional connections within and between brain networks in typical adolescence. The project also proposes to directly test whether these genetic factors jointly influence these imaging phenotypes and psychosis risk in clinical samples. To meet the research goals of the project, I require formal training in genomics and transcriptomics approaches (and especially their intersection with neuroimaging research). The primary mentorship team (Drs Pearlson and Glahn) has specific expertise in imaging-genomics in clinical datasets, as well as extensive experience as successful research mentors. Other key contributors and consultants provide expertise in imaging-transcriptomics (Dr Holmes), developmental neuroimaging (Dr Satterthwaite), data and network science (Dr Bassett), developmental transcriptomics (Dr Geschwind) and statistical genetics (Dr Blangero). This proposal will provide me with the direct training in research methodology and career support that is required for me to become a fully independent investigator, using tools from neuroimaging, genomics and transcriptomics to investigate psychosis pathogenesis.

项目总结/摘要 作为一名计算精神病学教师候选人，在神经成像和定量方面具有很强的背景， 数据分析，我寻求指导支持，将遗传和转录组学数据纳入我的工作，在我的 作为一名独立的调查员。我提出了一个人类神经成像交叉点的项目， 基因组学和转录组学，使用网络理论的计算工具来研究 精神分裂症和其他慢性精神病。 先前的研究表明，青春期突触的过度修剪破坏了功能和结构 大脑网络内的连通性，引起症状和功能障碍， 精神分裂症这一过程是发育过程中遗传和环境因素相互作用的产物， 并且它反映在结构和功能神经成像中观察到的改变中。网络分析 这些方法允许人们更深入地了解网络功能中干扰的性质， 这与将复杂疾病与单个大脑区域、基因或蛋白质联系起来的简单尝试形成了鲜明对比。项目 使用成像基因组学方法来测试是否与精神分裂症有关的基因网络 通过对常见遗传变异的全基因组研究， 突触完整性-影响皮质厚度的发展和内部的功能连接， 大脑网络之间的联系该项目还建议直接测试这些 遗传因素共同影响这些影像学表型和临床样本中的精神病风险。 为了达到项目的研究目标，我需要在基因组学和转录组学方面接受正式培训 方法（尤其是它们与神经影像学研究的交叉点）。初级指导团队（Drs Pearlson和Glahn）在临床数据集中的成像基因组学方面具有特定的专业知识， 作为成功的研究导师。其他主要贡献者和顾问提供以下方面的专业知识： 成像-转录组学（Holmes博士），发育神经成像（Satterthwaite博士），数据和网络 科学（Bassett博士），发育转录组学（Geschwind博士）和统计遗传学（Blangero博士）。 这项建议将为我提供研究方法和职业支持方面的直接培训， 我需要成为一个完全独立的研究者，使用神经成像，基因组学和 转录组学研究精神病发病机制。

项目成果

Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance.

性染色体剂量的改变会引起皮质解剖学和解剖协方差的协调变化。

• DOI: 10.1093/cercor/bhz235
• 发表时间: 2020
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Xenophontos,Anastasia;Seidlitz,Jakob;Liu,Siyuan;Clasen,LivS;Blumenthal,JonathanD;Giedd,JayN;Alexander-Bloch,Aaron;Raznahan,Armin
• 通讯作者: Raznahan,Armin