Genetics of Brain Structure and Function

描述（由申请人提供）：本项目的目标是确定与大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大脑疾病和精神疾病的基因。我们相信，在随机抽样的扩展家系中分析遗传对大脑结构和功能的影响，将为涉及正常和病理性大脑功能的基因提供重要线索。该项目的重点是对定量内表型的遗传解剖，这些内表型比离散疾病状态本身更直接地指示大脑功能的潜在生物学基础。为此，我们将对过去15年来一直参与我们正在进行的遗传研究的墨西哥裔美国人进行神经成像和神经心理学检查。所有参与者先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和神经认知变量的相关性。我们的具体目标是：1）对大约30个大家族的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脑相关表型的定量遗传结构，3）将特定的脑形态学变量和定量的白细胞衍生的基因表达测量分类为与脑功能相关的内表型，4）通过使用方差分量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中的变异的QTL，5）使用客观优先化策略来细化定位的QTL的位置并鉴定位置候选基因座，所述策略联合利用计算机生物信息学、遗传和转录数据，和6）鉴定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的John Blangero博士以及位于圣安东尼奥的德克萨斯大学健康科学中心的大卫·格拉恩博士和彼得·福克斯博士的协调R 01申请。如果获得资助，我们的数据和生物材料将被纳入NIMH人类遗传学计划，使其可供更广泛的科学界的合格研究人员使用。与机构使命的相关性：与大脑有关的精神疾病是一个主要的公共卫生负担，其生物学仍然在很大程度上是未知的。通过识别与大脑功能和结构有关的基因，我们将为这些疾病的决定因素提供新的生物学候选人，从而提高干预的潜力。

DESCRIPTION (provided by applicant): 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. To this end, 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. If funded, our data and biomaterials will be incorporated into the NIMH Human Genetics Initiative making them available to qualified researchers in the wider scientific community. Relevance to agency mission: 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.