International Multi-Center ADHD Genetics Project

描述（由申请人提供）：两个领域已被有力地牵连 注意缺陷多动障碍的病因学和病理生理学 （ADHD）。首先，家庭、双胞胎和收养研究表明， 遗传因素在其病因学中起重要作用。分离分析 而分子遗传学研究进一步支持了 ADHD的遗传因素第二，虽然ADHD的细节？S 病理生理学还有待研究，许多研究表明， 注意力缺陷多动障碍患者的生理异常这些异常现象 在神经心理学评估中， 就像神经影像学研究一样 现有的数据强烈表明，ADHD的一个重要组成部分？S 病因学由中枢神经系统中的基因表达介导。然而，在这方面， 要详细了解多动症的遗传学，必须克服几个障碍。 其中最重要的是ADHD中遗传异质性的可能性。 以及该疾病的子形式具有复杂模式的可能性， 传承这项研究的主要目标是检测一种或多种 负责ADHD遗传传递的基因。 该方案的主要策略是进行数量性状基因座（QTL）定位 使用400个微卫星标记（简单序列）进行同胞配对分析 重复序列（SSR）以10厘摩（cm）的间隔跨越基因组。这是 预计将确定人类基因组中含有ADHD QTL的区域， 为精细定位奠定基础，以确定一个或多个基因， 介导ADHD的易感性。该提案的三个目标是： 确定一个大样本的同胞对一致和不一致的多动症， 将QTL连锁作图方法应用于ADHD，并为 ADHD基因的精细定位该项目将利用一个合作 框架，以确定在八个共800兄弟姐妹对 国家收集如此大规模的国际样本将提供 检测基因效应的预期大小所需的统计能力，并将 创造800个核心家庭的资源，适合未来的家庭为基础的 关联研究以及随后的精细定位和全基因组关联 ADHD基因图谱

DESCRIPTION (provided by applicant): Two domains have been robustly implicated in the etiology and pathophysiology of attention deficit hyperactivity disorder (ADHD). First, family, twin, and adoption studies have demonstrated that genetic factors play a substantial role in its etiology. Segregation analysis and molecular genetic studies have provided further support for a significant genetic component in ADHD. Second, although the details of ADHD?s pathophysiology have yet to be worked out, numerous studies have demonstrated biological abnormalities among ADHD patients. These abnormalities have been demonstrated both indirectly, as in neuropsychological assessment, and directly as in neuroimaging studies. The available data strongly suggest that a substantial component of ADHD?s etiology is mediated by gene expression in the central nervous system. However, a detailed understanding of the genetics of ADHD must overcome several hurdles. Paramount among these are the potential for genetic heterogeneity among ADHD and the likelihood that subforms of the disorder have a complex mode of inheritance. The main goal of the proposed research is to detect one or more genes responsible for the genetic transmission of ADHD. The main strategy of this proposal is to perform quantitative trait locus (QTL) sibling pair analysis using 400 microsatellite markers (simple sequence repeats, SSRs) which span the genome at 10 centimorgan (cm) intervals. This is expected to identify regions in the human genome containing QTLs for ADHD and to lay the foundations for fine mapping to identify one or more genes that mediate the susceptibility to ADHD. The three aims of the proposal are to ascertain a large sample of sib-pairs concordant and discordant for ADHD, to apply QTL linkage mapping approach to ADHD, and to create a resource for the fine mapping of ADHD genes. The project will make use of a collaborative framework in order to ascertain a total of 800 sibling pairs in eight countries. The collection of such a large international sample will provide the statistical power needed to detect the expected size of gene effects, and will create a resource of 800 nuclear families suitable for future family-based association studies and for subsequent fine mapping and genomewide association mapping of ADHD genes.