Identification of genetic determinants of schizophrenia related phenotypes

描述（由申请人提供）：拟议研究的目标是识别和功能表征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标，反映了表征良好的神经元回路的功能。他们通常患有精神分裂症、双相情感障碍、自闭症、注意力缺陷障碍、亨廷顿舞蹈病等神经精神疾病。我们建议使用已有的2000多名具有认知表现数据的年轻健康男性样本和来自精神分裂症内表型遗传学协会（COGS）的公开样本进行有效的三期基因组全关联研究（GWAS），最大限度地提高我们的能力，同时最大限度地减少假阳性结果的可能性。我们的主要分析将集中在两个领域，执行功能和眼动功能，包括6种表型：表现准确性，表现速度，自愿性扫视运动速度，抑制功能，眼球追踪系统功能和反应时间变异性。第二阶段的探索性分析将考察潜在因素的关联，这些潜在因素反映了任务之间的共同因素和另外两种表型，即注视任务中的扫视频率，可能反映了与反扫视任务和开环追求功能相似的抑制功能。在我们的主要分析中发现的变异将通过测序、计算机分析、体外分析和死后脑样本的基因转录分析进一步探索，以指出特定的功能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卫生效益。识别影响认知方面的基因已经与特定的神经回路联系在一起，这将对我们对大脑功能的认识和理解有很大的好处，将神经科学和遗传学联系在一起。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谜团。本研究的另一个重要贡献将是通过数据共享。关于认知表型，这些数据不仅将揭示第一个基因，而且可用于未来的项目，以纳入强大的研究设计。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，促进对每种疾病和相关脑功能障碍的更好理解。为了最大限度地发挥这些优势，我们特别注意提供跨基因分型平台的数据信息，这些数据将通过NIMH存储库与我们的表型数据一起共享。

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.