Genetics of Attention Deficit-Hyperactivity Disorder

描述(申请人提供)：分子遗传学的最新进展极大地扩展了神经/行为障碍的遗传病因学和病理生理学研究的潜力。本应用侧重于常见的神经行为障碍，注意缺陷多动障碍(ADHD)。对ADHD分子遗传学基础的研究提供了候选基因方法的成功范例，通过多次重复和荟萃分析证实了ADHD与D4多巴胺受体(DRD4)基因和多巴胺转运体(DAT1)基因的等位基因之间的关联。对其他基因的单独研究(例如，DRD2、DRD3、DRD5、MAO和SNAP25基因座)也表明了ADHD的作用。我们建议在ADHD的多模式治疗(MTA)研究中，严格复制关联研究结果与大量具有良好特征的儿童样本。此外，为了超越相关性研究来调查实际的基因-表型关系，我们建议在神经心理功能、治疗反应和长期结果的研究中使用基因作为一个自变量来评估功能意义。我们的具体目标是：1.收集MTA受试者、对照同学和所有可用的家长的DNA(原始样本分别为579和288)。2.复制和扩展以DRD4-7R和DAT-1or开始的候选基因的关联研究。我们将把已发表的发现(基于ADHD的定性诊断)扩展到严重程度和认知障碍的量化测量。3.在随访评估中使用父母和教师的SNAP评定量表，将基因与预后和治疗反应联系起来。重要的问题是DRD4基因型别与对药物和心理社会治疗的反应以及与长期结果的关系。4.研究除DRD4和DAT外，在多巴胺途径中的多个基因，包括DRD1、DRD2、DRD3、DRD5和TH。“基因组单倍型”指的是位于一个以上基因座的单倍型，将被定义并测试基因之间可能的交互作用。

DESCRIPTION (provided by applicant): Recent advances in molecular genetics have greatly expanded the potential for studies of the genetic etiology and pathophysiology of neurological/behavior disorders. This application focuses on the common neurobehavioral disorder, Attention Deficit Hyperactivity Disorder (ADHD). Research on the molecular genetic bases of ADHD provides successful examples of the candidate gene approach, with association confirmed (by multiple replications and metaanalyses) between ADHD and alleles of the D4 dopamine receptor (DRD4) gene and the dopamine transporter (DAT1) gene. Single studies for other genes (e.g., the DRD2, DRD3, DRD5, MAO, and SNAP25 loci) also suggest a role in ADHD. We propose a rigorous replication of the association findings with the large well-characterized sample of children in the Multimodality Treatment of ADHD (MTA) study. Also, to go beyond the association studies to investigate the actual genotype - phenotype relationships, we propose to evaluate the functional significance by using genotype as an independent variable in studies of neuropsychological function, response to treatment, and long-term outcome. Our specific aims are: 1. Collect DNA from MTA subjects, control classmates, and all available parents (n = 579 and 288 respectively for the original samples). 2. Replicate and extend the association studies with candidate genes starting with DRD4-7R and DAT-1OR. We will extend the published findings (based on the qualitative diagnoses of ADHD) to quantitative measures of severity and cognitive impairment. 3. Relate genotype to outcome and treatment response through use of the SNAP rating scale from parents and teachers at follow-up assessment. The important question is the relationship of the DRD4 genotypes and response to pharmacological and psychosocial treatments and to long-term outcome. 4. To investigate multiple genes in the dopamine pathway in addition to DRD4 and DAT including DRD1, DRD2, DRD3, DRD5 and TH. "Genomic haplotypes", meaning haplo-specific genotypes at more than one locus, will be defined and tested for possible interactive roles among the genes.