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

项目摘要/摘要 作为计算精神病学系候选人，在神经成像和量化方面有很强的背景 数据分析，我寻求指导-支持在我的工作期间将遗传和转录数据纳入我的工作 作为一名调查员走向独立的道路。我提出了一个在人类神经成像的交叉点的项目， 基因组学和转录组学，使用网络理论的计算工具来调查 精神分裂症和其他形式的慢性精神病。 先前的工作表明，青春期突触过度修剪会破坏功能和结构 大脑网络内的连通性，引起与以下相关的症状和功能障碍 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， 它反映在结构和功能神经成像中观察到的变化中。基于网络的分析 方法允许人们对网络功能中干扰的性质提取更深层次的见解 与更简单的将复杂疾病与单一大脑区域、基因或蛋白质联系起来的尝试形成对比。该项目 使用成像基因组学方法来测试与精神分裂症有关的基因网络 对常见基因变异进行全基因组研究的风险--在许多情况下被证明是相关的 突触完整性--影响大脑皮质厚度的发育和大脑皮质内的功能联系 在典型的青春期大脑网络之间。该项目还提议直接测试这些 在临床样本中，遗传因素共同影响这些成像表型和精神病风险。 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进行正式培训 方法(特别是它们与神经成像研究的交叉)。主要指导团队(DRS Pearlson和Glahn)在临床数据集的成像基因组学方面拥有特定的专业知识，以及广泛的 作为成功的研究导师的经验。其他主要贡献者和顾问在以下方面提供专业知识 成像-转录学(霍姆斯博士)、发育神经成像(萨特思韦特博士)、数据和网络 科学(巴西特博士)、发育转录学(格施温德博士)和统计遗传学(布兰杰罗博士)。 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，即 我需要成为一名完全独立的调查员，使用神经成像、基因组学和 转录组学研究精神病的发病机制。

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.