International Multi-Center ADHD Genetics Project

描述(申请人提供)：涉及两个领域 注意缺陷多动障碍的病因学和病理生理学 (ADHD)。首先，家庭、双胞胎和收养研究已经证明 遗传因素在其病因中起着重要作用。偏析分析 分子遗传学研究为一种重要的 多动症的遗传成分。第二，虽然ADHD的细节是什么？S 许多研究表明，病理生理学还有待研究。 注意缺陷多动障碍患者的生物学异常。这些反常现象一直是 既有间接的，如在神经心理评估中，也有直接的 就像神经成像研究一样。 现有数据有力地表明，ADHD的一个重要组成部分？S 病因是由中枢神经系统中的基因表达介导的。然而， 要详细了解ADHD的遗传学，必须克服几个障碍。 其中最重要的是ADHD的遗传异质性的可能性。 这种疾病的亚型可能有一种复杂的 继承。拟议研究的主要目标是检测一个或多个 负责ADHD遗传传播的基因。 这一建议的主要策略是进行数量性状基因座(QTL) 400个微卫星标记的同胞配对分析(简单序列 重复，SSR)，这些SSR以10厘米的间隔跨越基因组。这是 有望确定人类基因组中包含ADHD和ADHD QTL的区域 为精细作图奠定基础，以识别一个或多个 调节ADHD的易感性。这项建议的三个目标是 确定ADHD的一致和不一致的同胞对的大样本， 将QTL连锁定位方法应用于ADHD，并为ADHD创建资源 ADHD基因的精细定位。该项目将利用一个协作性的 框架，以确定8个兄弟姐妹中的总共800对 国家。收集如此大量的国际样本将提供 检测基因效应的预期大小所需的统计能力，并将 创建适合未来以家庭为基础的800个核心家庭的资源 关联研究以及随后的精细作图和全基因组关联 注意缺陷多动障碍基因的定位。

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.