GWAS NEUROGENETICS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 大脑的结构和功能有很大的个体差异。发现这种变异的决定因素不仅会促进我们对正常大脑发育的了解，还会进一步加深我们对影响大脑的发育障碍和疾病的理解。这项应用的长期目标是表征基因和环境在塑造大脑结构和功能方面的不同作用，定位和识别涉及的基因，并表征大脑相关基因多态的影响。我们将收集700对澳大利亚双胞胎和他们的非双胞胎独生子女(年龄在20-26岁)的遗传信息样本的结构图像，我们之前已经从他们那里获得了认知功能的测量，我们已经对他们进行了广泛的基因分型。使用最先进的脑图技术，我们将建立遗传结构，并展示遗传效应对大脑形态测量的影响轨迹(特定目标1)。除了结构磁共振成像，双胞胎和他们的兄弟姐妹将参与扩散张量(DTI)(特定目标2)和功能(功能磁共振成像(FMRI)成像(特定目标3)。我们的大脑图谱技术将首次扩展到模拟遗传和非遗传对白质微结构的影响，并揭示遗传地形图。这项功能成像研究将应用广泛使用的N-back工作记忆任务，因为这是与认知能力的个体差异最直接相关的过程。我们将评估遗传调节的程度，并生成工作记忆过程中神经元活动的第一个详细遗传率图。将使用双胞胎/兄弟姐妹协方差的多变量遗传模型来估计遗传因素对区域大脑结构、与工作记忆相关的大脑激活区域和认知能力之间的协方差的相对贡献(特定目标4)。全基因组链接和关联扫描(在其他地方资助)将用于确定有助于大脑形态测量和功能遗传性的遗传位点(具体目标5)。我们还将使用同胞对等位基因关联分析(特定目标6)来筛选三个与大脑相关的遗传多态对选定的神经表型的影响。没有其他的双胞胎成像研究专门设计使用这种QTL作图策略，由于使用了现有的基因分型良好的样本，这将显著节省成本。最终目标是为今后的调查提供独特和有价值的资源基础(具体目标7)。这项研究的结果将为影响大脑结构和功能变异的遗传机制提供基本信息。这将为认知功能的个体差异和大脑疾病的脆弱性的起源提供新的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is great individual variation in the structure and function of the brain. Discovering the determinants of this variation will not only advance our knowledge of normal brain development, but further our understanding of developmental disorders and diseases that affect the brain. The long-term objective of this application is to characterize the differential roles of genes and environment in shaping brain structure and function, to map and identify the genes involved, and to characterize the impact of brain relevant genetic polymorphisms. We shall collect structural images on a genetically informative sample of 700 Australian twins and their non-twin singleton siblings (aged 20-26 yrs) from whom we have previously obtained measures of cognitive functioning, and for whom we have extensive genotyping already available. Using state-of-the-art brain mapping techniques we will establish the genetic architecture and show the trajectory of genetic effects on brain morphometry (Specific Aim 1). In addition to structural MRI, twins and their siblings will participate in diffusion tensor (DTI) (Specific Aim 2) and functional (fMRI) imaging (Specific Aim 3). Our brain mapping techniques will be extended, for the first time, to model genetic and non-genetic influences on white matter micro-structure, and to reveal the genetic topography. The functional imaging study will apply the widely used 'N-back' working memory task, since this is the process most directly linked to individual differences in cognitive ability. We shall assess the extent of genetic mediation and generate the first detailed heritability maps of neuronal activity during working memory. Multivariate genetic modeling of twin/sibling covariance will be used to estimate the relative contributions of genetic factors to co-variance between regional brain structures, areas of working memory-related brain activation, and cognitive ability (Specific Aim 4). Genome-wide linkage and association scans (funded elsewhere) will be used to identify genetic loci that contribute to heritability of brain morphometry and functioning (Specific Aim 5). We will also screen three brain relevant genetic polymorphisms for affects on selected neural phenotypes using sib-pair allelic association analysis (Specific Aim 6). No other imaging study in twins has been designed specifically to use such a QTL-mapping strategy, and this will be at marked cost savings due to the employment of an existing well-genotyped sample. A final aim is to provide a unique and valuable resource base for future investigation (Specific Aim 7). The results of this study will provide fundamental information on genetic mechanisms influencing variation in brain structure and function. This will provide new insights into the origin of individual differences in cognitive functioning and vulnerability to brain disorders.