GENETICS OF BRAIN STRUCTURE AND FUNCTION

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 2007年 目的：该项目的目标是确定与大脑结构和功能变化相关的数量性状基因座。 这项研究的最终希望是发现易患大脑疾病和精神疾病的基因。 我们相信，在随机抽样的扩展谱系中分析遗传对大脑结构和功能的影响将为有关正常和病理大脑功能所涉及的基因提供重要线索。该项目的重点是定量内表型的基因剖析，它比离散的疾病状态本身更直接地反映了大脑功能的潜在生物学基础。 研究计划和方法：我们将对墨西哥裔美国人进行神经影像学检查和神经心理学检查，这些人在过去 15 年中一直是我们正在进行的基因研究的一部分。 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组数据与神经解剖学和神经认知变量相关。我们的具体目标是：1) 对大约 30 个大家庭成员的 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) 通过估计其遗传力和遗传相关性来评估大脑相关表型的定量遗传结构，3) 将特定的大脑形态变量和定量白细胞衍生的基因表达测量分类为与大脑功能相关的内表型，4) 定位影响变异的 QTL通过使用方差分量方法进行基于连锁的基因组扫描来定量脑相关表型，5) 细化局部 QTL 的位置，并使用联合利用计算机生物信息学、遗传和转录数据的客观优先策略确定位置候选基因座，6) 识别两个最佳位置候选基因内最可能的功能变异。该项目涉及来自西南生物医学研究基金会 John Blangero 博士和 Drs. John Blangero 的协调 R01 应用程序。 David Glahn 和 Peter Fox，德克萨斯大学圣安东尼奥健康科学中心。 我们的数据和生物材料将纳入 NIMH 人类遗传学计划，使其可供更广泛科学界的合格研究人员使用。 临床相关性：与大脑相关的精神疾病是一个主要的公共卫生负担，其生物学特性仍然很大程度上未知。通过鉴定涉及大脑功能和结构的基因，我们将为此类疾病的决定因素提供新的生物学候选物，从而提高干预的潜力。

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. 2007 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. RESRARCH 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.