Genetics of Attention Deficit-Hyperactivity Disorder

描述（由申请人提供）：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。这个应用程序的重点是常见的神经行为障碍，注意缺陷多动障碍（ADHD）。对ADHD分子遗传基础的研究为候选基因方法提供了成功的例子，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）基因等位基因之间的关联。对其他基因（如DRD2、DRD3、DRD5、MAO和SNAP25基因座）的单一研究也表明在ADHD中起作用。我们建议在ADHD多模式治疗（MTA）研究中对大量具有良好特征的儿童样本进行严格的关联研究。此外，为了超越关联研究来研究实际的基因型-表型关系，我们建议通过将基因型作为神经心理功能、治疗反应和长期结果研究中的独立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父母的DNA（原始样本n = 579和288）。2. 从DRD4-7R和DAT-1OR开始，重复并扩展候选基因的关联研究。我们将把已发表的研究结果（基于ADHD的定性诊断）扩展到严重程度和认知障碍的定量测量。3. 通过使用家长和老师在随访评估中提供的SNAP评分量表，将基因型与结果和治疗反应联系起来。重要的问题是DRD4基因型与药物和社会心理治疗的反应以及长期结果之间的关系。4. 研究除DRD4和DAT外，多巴胺通路中包括DRD1、DRD2、DRD3、DRD5和TH的多个基因。“基因组单倍型”，即多个基因座上的单倍型特异性基因型，将被定义并测试基因之间可能的相互作用。

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.