Genetic influences on the brain: A twin imaging study

描述（由申请人提供）：大脑的结构和功能存在很大的个体差异。发现这种变异的决定因素不仅会提高我们对正常大脑发育的认识，而且会加深我们对影响大脑的发育障碍和疾病的理解。本申请的长期目标是表征基因和环境在塑造脑结构和功能中的不同作用，绘制和鉴定所涉及的基因，并表征脑相关遗传多态性的影响。我们将收集700名澳大利亚双胞胎和他们的非双胞胎单胞胎兄弟姐妹（年龄20-26岁）的遗传信息样本的结构图像，我们以前从他们那里获得了认知功能的测量结果，并且我们已经为他们提供了广泛的基因分型。使用最先进的脑映射技术，我们将建立遗传结构，并显示遗传对脑形态测量学的影响轨迹（具体目标1）。除了结构MRI，双胞胎和他们的兄弟姐妹将参加扩散张量（DTI）（特定目的2）和功能（fMRI）成像（特定目的3）。我们的大脑绘图技术将首次扩展到模拟遗传和非遗传对白色物质微观结构的影响，并揭示遗传地形图。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，并生成第一个详细的工作记忆过程中神经元活动的遗传力图。将使用双胞胎/同胞协方差的多变量遗传建模来估计遗传因素对局部脑结构、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（具体目标4）。全基因组连锁和关联扫描（其他地方资助）将用于识别有助于脑形态和功能遗传的遗传位点（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）筛选三种脑相关遗传多态性对选定神经表型的影响。没有其他双胞胎的影像学研究专门设计使用这样的QTL定位策略，这将是在显着的成本节省，由于就业的现有良好的基因型样本。最后一个目标是为今后的调查提供一个独特而有价值的资源基础（具体目标7）。这项研究的结果将提供影响大脑结构和功能变化的遗传机制的基本信息。这将为认知功能和大脑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.