Mapping Genes for Neurocognitive Endophenotypes

描述（由申请人提供）： 这项研究将试图绘制一些已知与精神分裂症和精神分裂症谱系障碍相关的神经认知特征的基因的染色体位置。最感兴趣的神经认知特征或内表型包括通过P50听觉诱发电位测量的感觉门控受损、通过连续执行任务测量的持续集中注意力和通过计算机视觉空间任务测量的工作记忆。内表型可以在正常人中测量，并且预计比精神分裂症的诊断更能代表基因作用的近端功能，从而促进其贡献基因座的定位。我们成功地定位内表型基因并不取决于极端表型个体的识别，而是取决于导致人群内表型正常变异的基因的效应大小。神经认知内表型将在尼泊尔东部的一个同质的、遗传隔离的人群中进行测量，该人群被称为吉瑞尔族。研究样本由2000个属于一个单一的六代扩展系谱，从他们的DNA已被收集和基因分型完成的个人。样本是对Jiri和Sikri山谷的四个村庄进行全面调查的结果;所有调查对象都是在不考虑任何疾病状况的情况下进行调查的。集中在一个大的扩展系谱从一个孤立的和种族同质的人口，并分析数量性状（神经认知内表型），利用方差分量分析方法的权力，将为我们提供了很好的权力，以定位相关的数量性状基因座（QTL）。在这个人群样本中绘制这些特征可能会识别出直接影响精神分裂症和其他疾病易感性的基因，甚至可能为寻找影响认知的基因提供信息。即使在基因本身被识别和克隆之前，这些相关性状的定位将在几个方面帮助和推进精神分裂症的研究。神经生理学特征的数据可能是有用的，客观地定义亚型的精神分裂症谱的病因更同质，并在一般情况下，在细化精神分裂症谱疾病分类学，相关的遗传研究的援助。此外，这些相关的内表型的映射将使更狭窄的重点搜索额外的易感基因，也将增加权力，以确定其他基因影响精神分裂症的易感性，使用条件分析。

DESCRIPTION (provided by applicant): This study will attempt to map the chromosomal locations of genes underlying some of the neurocognitive traits that are known to be associated with schizophrenia and schizophrenia spectrum disorders. The neurocognitive traits, or endophenotypes, of greatest interest include impaired sensory gating as measured by the P50 auditory evoked potential, sustained focused attention, as measured by the continuous performance task, and working memory, as measured by computerized visuospatial tasks. The endophenotypes can be measured in normals and are expected to represent more proximal functions of gene action than the diagnosis of schizophrenia, thus facilitating the localization of their contributing loci. Our success in mapping genes for the endophenotypes does not depend on identification of individuals with extreme phenotypes but on the effect sizes of the genes contributing to normal variation in the endophenotypes in the population. The neurocognitive endophenotypes will be measured in a homogeneous, genetically isolated population in eastern Nepal, an ethnic group known as the Jirels. The study sample consists of 2000 individuals belonging to a single six-generation extended pedigree, from whom DNA has been collected and genotyping completed. The sample is the result of a complete ascertainment of four villages in the Jiri and Sikri valleys; all subjects were ascertained without regard to any disease status. Focusing on a large extended pedigree from an isolated and ethnically homogeneous population, and analyzing quantitative traits (the neurocognitive endophenotypes) by exploiting the power of variance components methods of analysis, will provide us with excellent power to map the relevant quantitative trait loci (QTLs). Mapping these traits in this population sample may identify genes that directly influence susceptibility to schizophrenia and other disorders and may even inform the search for genes that influence cognition. Even before the genes themselves are identified and cloned, the mapping of these correlated traits will aid and advance schizophrenia research in several ways. The neurophysiological trait data may be useful for objectively defining subtypes of the schizophrenia spectrum that are more etiologically homogeneous, and in general, aid in the refinement of schizophrenia spectrum nosology, relevant for genetic studies. In addition, the mapping of these correlated endophenotypes will enable more narrowly focused searches for additional susceptibility genes, and will also increase the power to identify additional genes influencing schizophrenia susceptibility, using conditional analyses.