Genetics of Attention Deficit-Hyperactivity Disorder

注意力缺陷多动症的遗传学

• 批准号: 7067155
• 负责人: JAMES M SWANSON
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067155
• 关键词: adolescence (12-20); attention deficit disorder; behavioral genetics; clinical research; dopamine receptor; dopamine transporter; genetic polymorphism; genotype; human subject; molecular genetics; neuropsychological tests; neuropsychology; pediatrics; polymerase chain reaction

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.

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。此应用程序侧重于常见的神经行为障碍，注意力缺陷多动障碍（ADHD）。对ADHD分子遗传基础的研究提供了候选基因方法的成功例子，ADHD与D4多巴胺受体（DRD 4）基因和多巴胺转运蛋白（DAT 1）基因的等位基因之间的关联得到了证实（通过多次重复和荟萃分析）。其他基因的单一研究（例如，DRD 2、DRD 3、DRD 5、MAO和SNAP 25基因座）也提示在ADHD中作用。我们建议在ADHD多模式治疗（MTA）研究中严格复制与大量特征良好的儿童样本相关的研究结果。此外，超越关联研究，调查实际的基因型-表型关系，我们建议使用基因型作为一个独立的变量，在神经心理功能，治疗反应和长期结果的研究，以评估功能的意义。我们的具体目标是：1.从MTA受试者、对照同学和所有可用的父母（原始样本分别为n = 579和288）收集DNA。2.从DRD 4 - 7 R和DAT-1 OR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.在随访评估时，通过使用父母和教师的SNAP评定量表，将基因型与结果和治疗反应联系起来。重要的问题是DRD 4基因型与药物和社会心理治疗反应以及长期结果的关系。4.研究多巴胺通路中除DRD 4和DAT外的多个基因，包括DRD 1、DRD 2、DRD 3、DRD 5和TH。“基因组单倍型”是指在一个以上的基因座上的单倍特异性基因型，将被定义和测试基因之间可能的相互作用。