Genetic influences on the brain: A twin imaging study

描述（由申请人提供）：大脑的结构和功能有很大的个体差异。发现这种差异的决定因素不仅会提高我们对正常大脑发育的认识，而且会进一步加深我们对影响大脑的发育障碍和疾病的理解。该应用程序的长期目标是表征基因和环境在塑造大脑结构和功能中的不同作用，绘制和识别相关基因，并表征大脑相关遗传多态性的影响。我们将收集700名澳大利亚双胞胎及其非双胞胎单胎兄弟姐妹（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，并且我们已经对他们进行了广泛的基因分型。使用最先进的脑图谱技术，我们将建立遗传结构，并显示遗传对脑形态测量的影响轨迹（具体目标1）。除了结构MRI外，双胞胎及其兄弟姐妹还将参与弥散张量（DTI） （Specific Aim 2）和功能（fMRI）成像（Specific Aim 3）。我们的大脑制图技术将首次扩展到模拟遗传和非遗传对白质微观结构的影响，并揭示遗传地形。功能成像研究将采用广泛使用的“N-back”工作记忆任务，因为这是与个体认知能力差异最直接相关的过程。我们将评估遗传调解的程度，并产生工作记忆期间神经元活动的第一个详细的遗传性图。双胞胎/兄弟姐妹协方差的多变量遗传模型将用于估计遗传因素对脑区域结构、工作记忆相关脑激活区域和认知能力之间协方差的相对贡献（Specific Aim 4）。全基因组连锁和关联扫描（由其他地方资助）将用于识别有助于大脑形态测量和功能遗传的遗传位点（具体目标5）。我们还将使用兄弟姐妹对等位基因关联分析筛选三种与大脑相关的遗传多态性对选定神经表型的影响（Specific Aim 6）。没有其他双胞胎成像研究专门设计使用这种qtl定位策略，由于使用现有的良好基因分型样本，这将显著节省成本。最终目标是为未来的调查提供一个独特而有价值的资源基础（具体目标7）。本研究结果将为研究影响大脑结构和功能变异的遗传机制提供基础信息。这将为认知功能和脑部疾病易感性的个体差异的起源提供新的见解。

DESCRIPTION (provided by applicant): 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.