Identification of genetic determinants of schizophrenia related phenotypes

精神分裂症相关表型遗传决定因素的鉴定

• 批准号: 7887655
• 负责人: Dimitrios Avramopoulos
• 金额: $ 68.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-23 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887655
• 关键词: Accounting; Age; Attention; Attention Deficit Disorder; Attention deficit hyperactivity disorder; Autistic Disorder; Back; Biological; Biomedical Research; Bipolar Disorder; Brain; Code; Cognition; Cognitive; Cognitive deficits; Communities; Computer Simulation; Copy Number Polymorphism; DNA; Data; Defect; Disease; Elements; Eye; Eye Movements; Frequencies; Functional disorder; Future; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genome; Genotype; Goals; Greek; Health Benefit; Human; Huntington Disease; In Vitro; Incidence; Individual; Knowledge; Link; Linkage Disequilibrium; Measures; Mental disorders; Movement; National Institute of Mental Health; Neurons; Neurosciences; Performance; Phenotype; Psychotic Disorders; Public Health; Reaction Time; Research; Research Design; Research Personnel; Resources; Saccades; Sampling; Schizophrenia; Short-Term Memory; Speed; Staging; System; Testing; Transcript; Variant; base; brain tissue; cognitive function; cost; data sharing; design; disorder risk; endophenotype; executive function; follow-up; genetic variant; genome wide association study; indexing; interest; male; neuronal circuitry; neuropsychiatry; performance tests; protein function; public health relevance; repository; response; sample fixation

DESCRIPTION (provided by applicant): The goal of the proposed study is to identify and functionally characterize genetic variation that physiologically influences basic cognitive phenotypes. The phenotypes of interest measure basic cognitive performance indexes, reflecting the function of well characterized neuronal circuits. They are often impaired in neuropsychiatric disorders like schizophrenia, bipolar disorder, autism, attention deficit disorder, Huntington's disease and others. We propose to use a pre-existing sample of over 2,000 young healthy males with cognitive performance data and the publicly available sample from the Consortium on the Genetics of Endophenotypes in Schizophrenia (COGS) for an efficient three stage genome wide association study (GWAS), maximizing our power while minimizing the possibility of false positive results. Our main analysis will focus in two domains, executive function and occulomotor function, including a total of 6 phenotypes: Performance accuracy, performance speed, voluntary saccade movement speed, inhibition function, eye pursuit system function and reaction time variability. Secondary exploratory analyses will examine associations with underlying latent factors reflecting common elements across tasks and two more phenotypes, the frequency of saccades in an eye fixation task, likely to reflect inhibition function similar to what is measured in the antisaccade task and the open loop pursuit function. Variants identified in our main analysis will be further explored through sequencing, in silico analyses, in vitro analyses and gene transcript analyses on post mortem brain samples in order to point to specific functional DNA variants and explore the biological mechanism through which they influence cognitive performance. Linking genes to cognitive phenotypes will have a significant impact on multiple aspects of biomedical research leading to important public health benefits. Identifying genes that influence aspects of cognition already linked to specific neuronal circuitry will be a considerable benefit to our knowledge and understanding of brain function, tying together neuroscience and genetics. The observed defects of these phenotypes in multiple psychiatric disorders suggests these results will also contribute to untangle the genetics of many psychiatric diseases. Another significant contribution of this study will be through data sharing. Regarding the cognitive phenotypes this data will not only uncover the first genes but also be available for future projects to incorporate into powerful study designs. Regarding the study of psychiatric disorders it will allow the examination of disease - associated DNA variants for effects on cognitive variables, promoting a better understanding of each disorder and the related brain dysfunctions. To maximize these benefits we have paid special attention to provide data informative across genotyping platforms that will be share together with our phenotype data through the NIMH repository. PUBLIC HEALTH RELEVANCE: This study aims to find genes involved in specific aspects of cognitive performance in humans. We have used standardized tasks to measure in about 2,000 individuals aspects of cognitive performance like speed and accuracy and eye movement control and we propose to analyze DNA variation across the genome, follow an efficient staged approach to locate genetic variants that influence these cognitive variables and explore the function of those genetic variants. An immediate benefit of this project will be to our understanding of the relationships between genes, neuronal circuitry and cognition. An additional and perhaps more important benefit will be to the study of the numerous psychiatric and other diseases that often perturb these same cognitive functions, including schizophrenia, autism, attention deficit disorder and many others.

描述（由申请人提供）：拟议研究的目的是识别并在功能上表征生理上影响基本认知表型的遗传变异。感兴趣的表型衡量基本认知性能指数，反映了特征良好的神经元电路的功能。它们通常在精神分裂症，躁郁症，自闭症，注意力缺陷障碍，亨廷顿氏病等神经精神疾病中受到损害。我们建议使用2,000多名具有认知绩效数据的超过2,000名年轻健康男性的样本，并使用来自精神分裂症（COGS）遗传学的联盟中的公开样本（COGS）的公开样本，以最大程度地降低我们的能力，同时最大程度地减少假阳性结果。我们的主要分析将集中在两个领域，即执行功能和Occulomotor功能，包括总共6个表型：性能准确性，性能速度，自愿扫视运动速度，抑制功能，眼球追击系统功能和反应时间变化。次要探索性分析将检查与反映跨任务和两个表型的共同元素的潜在潜在因素的关联，这是眼固定任务中扫视的频率，这可能反映了抑制功能，类似于反accade任务中测量的抑制作用和开放式循环追踪功能。在我们的主要分析中确定的变体将通过测序，在硅分析中，体外分析和基因转录分析对验尸后脑样本进行测序，以指出特定的功能性DNA变异，并探索它们影响认知性能的生物学机制。 将基因与认知表型联系起来将对生物医学研究的多个方面产生重大影响，从而带来重要的公共卫生益处。识别影响已经与特定神经元电路相关的认知方面的基因将是我们对脑功能的知识和理解，并将神经科学和遗传学联系在一起的可观好处。这些表型在多种精神疾病中观察到的缺陷表明这些结果也将有助于解开许多精神病的遗传学。 这项研究的另一个重要贡献将是通过数据共享。关于认知表型，此数据不仅可以揭示第一个基因，而且还可以供将来的项目纳入强大的研究设计中。关于精神疾病的研究，它将允许检查疾病 - 相关的DNA变异，以影响认知变量，从而更好地了解每种疾病和相关的脑功能障碍。为了最大程度地利用这些好处，我们特别关注的是，在基因分型平台上提供了数据提供信息，这些平台将通过NIMH存储库与我们的表型数据共享。 公共卫生相关性：本研究旨在找到参与人类认知表现特定方面的基因。我们已经使用了标准化任务来测量约2,000个个人认知表现方面的方面，例如速度，准确性和眼动控制，我们建议分析整个基因组的DNA变异，遵循有效的分阶段方法来定位影响这些认知变量的遗传变异，并探索这些遗传变异的功能。该项目的直接好处将是我们理解基因，神经元电路和认知之间的关系。对众多精神病和其他疾病的研究，这些疾病经常会使这些相同的认知功能（包括精神分裂症，自闭症，注意力缺陷障碍等）扰动，这是一个额外的更重要的好处。