Mapping Genes for Neurocognitive Endophenotypes

描述(由申请人提供)： 这项研究将试图绘制出与精神分裂症和精神分裂症谱系障碍相关的一些神经认知特征背后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P50听觉诱发电位测量的感觉门控受损，持续执行任务测量的持续集中注意力，以及计算机化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，并有望比精神分裂症的诊断更能代表基因作用的近端功能，从而有助于定位它们的贡献基因。我们成功地定位内表型的基因并不取决于对具有极端表型的个体的识别，而是取决于导致群体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一个同质的、基因上孤立的群体中进行测量，这个民族被称为吉瑞尔人。研究样本包括2000个个体，属于一个单一的六代延伸家系，从这些个体中收集DNA并完成基因分型。该样本是对吉里和锡克里山谷的四个村庄进行彻底查明的结果；所有受试者都是在不考虑任何疾病状况的情况下确定的。关注一个孤立和种族同质的群体中的一个大的扩展家系，并利用方差成分分析方法来分析数量性状(神经认知内表型)，将为我们定位相关的数量性状基因座(QTL)提供极好的能力。在这个人群样本中绘制这些特征可能会识别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，这些相关特征的定位将在几个方面帮助和推进精神分裂症的研究。神经生理学特征数据可能有助于客观地定义精神分裂症谱的亚型，这些亚型在病因上更相似，通常有助于完善与遗传学研究相关的精神分裂症谱病因学。此外，这些相关内表型的图谱将使更狭隘地搜索其他易感基因成为可能，并将增加使用条件分析识别影响精神分裂症易感性的其他基因的能力。

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.