Pathway(s) From Genes to Functional Deficits of Schizophrenia Patients

描述(由申请人提供)：该RFA支持旨在寻找与功能性“与患者、他们的家人和决策者相关的行为表型”相关基因的研究。作为对这一RFA的回应，这一应用程序将扩展有关精神分裂症遗传学的现有信息体，并将独特的重点放在了解精神分裂症患者功能缺陷的遗传基础上。PI组建了一支由精神分裂症研究、功能评估、神经生理学和神经认知评估、统计遗传学和结构方程建模领域的专家组成的团队。研究团队将通过两个成熟和高效的精神分裂症研究计划获得大量现有的基础设施和患者资源。400名精神分裂症患者和100名非精神病学对照受试者(NC)将接受临床、神经认知、神经生理学和多维功能评估。从这些功能评估中，精神分裂症患者的核心和可分离的功能缺陷将通过主成分分析(PCA)来识别。PCA将捕捉导致精神分裂症患者面临困难的缺陷的核心特征，因为他们在现实世界日常生活中通过迷宫般的功能挑战进行导航。这些特征将被用作了解这种疾病中潜在的功能损害的复杂遗传结构的一种手段。从基因到功能的途径，包括可能的调节和调节神经生物学和神经心理过程，然后将通过结构方程建模来确定。因此，这项工作的一个关键最终成果将是识别精神分裂症患者的核心功能缺陷，并指定显著导致这些核心功能缺陷的基因，以便解释基因功能和基因影响行为从而调节现实世界功能的可能生物学途径。

DESCRIPTION (provided by applicant): This RFA supports studies designed to find genes that relate to functional "behavioral phenotypes of relevance to patients, their families, and policymakers." In response to this RFA, this application will extend the existing body of information regarding the genetics of schizophrenia with a unique focus on understanding the genetic basis for functional deficits in schizophrenia patients. The PI has assembled a team of experts in the areas of schizophrenia research, functional assessment, neurophysiological and neurocognitive assessment, statistical genetics and structural equation modeling. The research team will have access to substantial existing infrastructure and patient resources via two mature and highly productive schizophrenia research programs. Cohorts of 400 schizophrenia patients and 100 nonpsychiatric comparison subjects (NCS) will be characterized by clinical, neurocognitive, neurophysiological, and multi- dimensional functional assessments. From these functional assessments, core and dissociable functional deficits in schizophrenia patients will then be identified via principal components analysis (PCA). PCA will capture the core features of the deficits that are responsible for the difficulties faced by schizophrenia patients as they "navigate" through a maze of functional challenges in real-world day-to-day living. These features will be used as a means of understanding the complex genetic architecture underlying functional impairment in this disorder. The pathways from gene to function, including possible mediating and moderating neurobiological and neuropsychological processes, will then be identified via structural equation modeling. Thus, one key final product of this work will be the identification of core functional deficits in schizophrenia patients and the specification of genes that substantially contribute to those core deficits so that both gene-function and the possible biological pathways by which genes impact behavior and thereby regulate real world functioning will be explicated.