多巴胺β-羟化酶基因与注意缺陷多动障碍及其候选内表型的关联研究

Attention-deficit/hyperactivity disorder (ADHD) is a common, etiologically heterogeneous complex disorder with high heritability. Synthesis of norepinephrine(NE) from dopamine(DA) is catalyzed by the enzyme dopamine β-hydroxylase(DβH), which is essential for the balance of DA/NE in cortical areas associated with ADHD and its cognitive functions (e.g. prefrontal cortex). Previous study of our team suggested that dopamine β-hydroxylase(DBH) gene is associated with ADHD and its endophenotypes (reaction time and interference control). Numerous polymorphisms in the DBH gene have been found to exert their direct influence on the plasma DβH activity (pDβH) independently, and pDβH varies between individuals but stable within subjects, which suggests pDβH as a good endophenotype of ADHD. In the present study, 1000 ADHD children (including 500-800 trios) and 500 sex- and age-matched unaffected controls will be enrolled with phenotype data, cognitive functions, genotypes of DBH gene and pDβH activity. The aim of this work is to assess the association between DBH gene and pDβH activity (especially in trios), the characteristics of pDβH activity in ADHD and its subtypes, and the association between pDβH activity and cognitive functions in ADHD and controls. We anticipate to find new biomarker and explore the etiology and pathogenesis of ADHD.

注意缺陷多动障碍是异质性很强的复杂遗传性疾病。多巴胺β-羟化酶(DβH)催化多巴胺(DA)转化为去甲肾上腺素(NE)，对维持与ADHD及其认知功能密切相关脑区(如前额叶)的 DA/NE平衡具有重要作用。本研究组前期关注于候选基因研究- - 发现多巴胺β羟化酶基因(DBH)可能与ADHD及其认知功能(反应时、干扰抑制能力)存在关联。血浆DβH活性主要受控于DBH基因，在个体间差异悬殊，但对同一个体则相对稳定，是研究ADHD较好的内表型之一。本研究拟纳入1000例患儿(含500-800核心家系)和500例正常对照，获得表型、认知功能资料，检测DBH基因型、血浆DβH活性，旨在探讨DBH基因与血浆DβH活性的关系(特别是在家系资料中)，探讨ADHD及其亚型的血浆DβH活性特点，以及ADHD和正常对照中认知功能与血浆DβH活性的关系。本项目预期发现ADHD新的生物标记，进而探讨ADHD潜在的病理机制。

注意缺陷多动障碍是异质性很强的复杂遗传性疾病。多巴胺β-羟化酶(DβH)催化多巴胺(DA)转化为去甲肾上腺素(NE)，对维持与ADHD及其认知功能密切相关脑区(如前额叶)的 DA/NE平衡具有重要作用。本研究组前期关注于候选基因研究——发现多巴胺β羟化酶基因(DBH)可能与ADHD及其认知功能(反应时、干扰抑制能力)存在关联。认知功能是研究ADHD较好的内表型之一。依据DSM-IV的诊断标准，进行ADHD临床诊断、亚型和共患病评定。共收集1395个ADHD核心家系、572例散发ADHD病例（父母未参与取血）957例正常对照的临床资料、认知功能测验资料（数字广度任务、Stroop色词命名任务）和静脉血标本。采用TaqManTM荧光探针杂交扩增的基因分型技术对DBH基因的8个多态性位点进行基因型检测。应用基于家系和病例对照样本资料中，采用基于家系的检验（FBAT）、卡方检验和单体型分析对ADHD及其表型进行关联分析，并对P值进行多重校正。采用基于家系的检验（FBAT）和协方差分析探讨基因与数字广度任务和stroop色词命名任务表现的关联情况。DBH基因多态性与ADHD存在关联，且这种关联具有性别特异性及亚型特异性。本研究发现：DBH基因的rs2073837多态性的A等位基因和rs129882多态性的C等位基因与ADHD存在关联。这种关联主要存在于男性ADHD、共患ODD等亚型中；rs1611115、rs1076150、rs2873804和rs1548364均与ADHD-HI存在关联；DBH基因可能与患者的执行控制功能相关联： DBH基因的rs2073837和rs129882多态与ADHD以冲突抑制为主的执行控制功能和以干扰抑制为主的工作记忆能力关联。