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）：拟议研究的目标是识别和功能表征在生理上影响基本认知表型的遗传变异。感兴趣的表型测量基本的认知表现指数，反映了充分表征的神经元回路的功能。他们经常因精神分裂症、双相情感障碍、自闭症、注意力缺陷障碍、亨廷顿舞蹈症等神经精神疾病而受损。我们建议使用 2,000 多名年轻健康男性的现有样本以及认知表现数据和来自精神分裂症内表型遗传学联盟 (COGS) 的公开样本进行有效的三阶段全基因组关联研究 (GWAS)，最大限度地发挥我们的力量，同时最大限度地减少误报结果的可能性。我们的主要分析将集中在执行功能和动眼功能两个领域，总共包括6种表型：表现准确性、表现速度、随意扫视运动速度、抑制功能、眼追踪系统功能和反应时间变异性。二次探索性分析将检查与反映跨任务和另外两种表型的共同元素的潜在潜在因素的关联，即注视任务中的眼跳频率，可能反映类似于反眼跳任务和开环追踪功能中测量的抑制功能。我们将通过对死后大脑样本进行测序、计算机分析、体外分析和基因转录本分析来进一步探索我们主要分析中确定的变异，以指出特定的功能性 DNA 变异并探索它们影响认知表现的生物学机制。 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健康益处。识别影响已经与特定神经元回路相关的认知方面的基因，将对我们对大脑功能的认识和理解，将神经科学和遗传学结合起来，大有裨益。在多种精神疾病中观察到的这些表型缺陷表明，这些结果也将有助于解开许多精神疾病的遗传学。 这项研究的另一个重要贡献是通过数据共享。关于认知表型，这些数据不仅将揭示第一个基因，而且还可用于未来的项目，以纳入强大的研究设计中。关于精神疾病的研究，它将允许检查与疾病相关的 DNA 变异对认知变量的影响，从而促进更好地了解每种疾病和相关的大脑功能障碍。为了最大限度地发挥这些优势，我们特别注重跨基因分型平台提供信息丰富的数据，这些数据将通过 NIMH 存储库与我们的表型数据一起共享。 公共健康相关性：本研究旨在寻找与人类认知表现特定方面相关的基因。我们使用标准化任务来测量大约 2,000 个人的认知表现，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让我们了解基因、神经元回路和认知之间的关系。另一个也许更重要的好处将是对许多精神疾病和其他疾病的研究，这些疾病经常扰乱这些相同的认知功能，包括精神分裂症、自闭症、注意力缺陷障碍和许多其他疾病。