GENETICS OF BRAIN STRUCTURE AND FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：本项目的目标是确定与脑结构和功能变异相关的数量性状基因座。这项研究的最终希望是发现易患脑部疾病和精神疾病的基因。我们相信，对随机抽样的扩展家系中的大脑结构和功能的遗传影响的分析将提供与正常和病理大脑功能相关的基因的重要线索。该项目的重点是定量内表型的遗传解剖，与离散疾病状态本身相比，这些内表型更直接地标示大脑功能的潜在生物学基础。 研究计划和方法：我们将对过去15年来一直参与我们正在进行的基因研究的墨西哥裔美国人进行神经成像和神经心理学检查。所有参与者之前都进行了基因分型，我们的计划是利用现有的基因组扫描和全基因组定量转录数据与神经解剖学和神经认知变量相关联。我们的具体目标是：1)对大约30个大家庭中的1,000名墨西哥裔美国人进行高质量的脑磁共振成像和神经心理学检查；2)通过估计他们的遗传性和它们的遗传相关性来评估脑相关表型的定量遗传结构；3)将特定的脑形态变量和定量白细胞衍生基因表达指标归类为与脑功能相关的内表型；4)通过使用方差分量方法进行基于连锁的基因组扫描来定位影响定量脑相关表型变异的QTL；5)利用在硅生物信息学、转录和基因数据中联合使用的客观优先策略来精炼定位QTL的位置并识别位置候选基因座6)确定两个最佳位置候选基因中最有可能的功能变异。该项目涉及西南生物医学研究基金会的John Blangero博士和圣安东尼奥的德克萨斯大学健康科学中心的David Glahn和Peter Fox博士协调的R01申请。我们的数据和生物材料将被纳入NIMH人类遗传学倡议，供更广泛科学界的合格研究人员使用。 临床意义：脑相关精神疾病是一种主要的公共卫生负担，其生物学特性在很大程度上仍不清楚。通过识别与大脑功能和结构有关的基因，我们将为此类疾病的决定因素提供新的生物学候选，从而提高干预的可能性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The goal of this project is to identify quantitative trait loci associated with variation in brain structure and function. The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses. We believe that the analysis of genetic influences on brain structure and function in randomly sampled extended pedigrees will provide significant clues regarding the genes that are involved in both normal and pathological brain function. The focus of the project is on the genetic dissection of quantitative endophenotypes that more directly index the underlying biological basis of brain function than do discrete disease states themselves. RESEARCH PLAN AND METHODS: We will perform neuroimaging and conduct neuropsychological examinations on Mexican American individuals who have been part of our ongoing genetic research studies for the past 15 years. All participants were previously genotyped and our plan is to utilize existing genome scan and genome-wide quantitative transcriptomic data for correlation with neuroanatomic and neurocognitive variables. Our specific aims are to: 1) perform high quality brain magnetic resonance imaging and neuropsychological examinations on 1,000 Mexican Americans who are members of approximately 30 large extended families, 2) assess the quantitative genetic architecture of brain-related phenotypes by estimating their heritabilities and their genetic correlations, 3) classify specific brain morphological variables and quantitative leukocyte-derived gene expression measures as endophenotypes related to brain function, 4) localize QTLs influencing variation in the quantitative brain-related phenotypes by performing linkage-based genome scanning using the variance component method, 5) refine the position of localized QTLs and identify positional candidate loci using an objective prioritization strategy that jointly utilizes in silico bioinformatics, genetic, and transcriptional data, and 6) identify the most likely functional variations within the two best positional candidate genes. This project involves coordinated R01 applications from Dr. John Blangero, Southwest Foundation for Biomedical Research, and Drs. David Glahn and Peter Fox, University of Texas Health Science Center at San Antonio. Our data and biomaterials will be incorporated into the NIMH Human Genetics Initiative making them available to qualified researchers in the wider scientific community. CLINICAL RELEVANCE: Brain-related mental diseases are a major public health burden whose biology is still largely unknown. By identifying genes involved in brain function and structure, we will provide novel biological candidates for the determinants of such diseases and thus improve potential for intervention.