Schellekens Arnt F A, Franke Barbara, Ellenbroek Bart, Cools Alexander, de Jong Cor A J, Buitelaar Jan K, Verkes Robbert-Jan
Donders Institute for Brain, Cognition, and Behaviour, Department of Psychiatry, Radboud University Nijmegen Medical Centre, the Netherlands.
Arch Gen Psychiatry. 2012 Apr;69(4):339-48. doi: 10.1001/archgenpsychiatry.2011.1335.
Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies.
To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity.
Case-control pharmacogenetic challenge study.
Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education.
Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers.
A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg).
Outcome measures were plasma growth hormone levels and results of a continuous performance task.
Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes.
COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.
酒精依赖是一种常见的具有高遗传性的神经精神疾病。然而，酒精依赖的基因关联研究常常受到结果无法重复的困扰。使用中间表型可能有助于明确各种候选基因的作用模式，并提高基因关联研究的可重复性。
测试中枢多巴胺受体敏感性作为酒精依赖的中间表型，具体评估多巴胺能基因COMT Val158Met和DRD2 Taq1A影响多巴胺受体敏感性的假设。
病例对照药物遗传学激发研究。
将因戒酒入院的酒精依赖患者与年龄和教育水平相匹配的健康对照者进行比较。
患者（n = 110）为连续样本，而对照者（n = 99）通过在当地报纸上刊登广告招募。
使用多巴胺激动剂盐酸阿扑吗啡（0.005 mg/kg）皮下注射进行多巴胺激发试验。
观察指标为血浆生长激素水平和持续性操作任务的结果。
酒精依赖患者的中枢多巴胺受体敏感性降低，且受多巴胺能基因调节。具体而言，DRD2 Taq1A基因型通过血浆生长激素水平影响多巴胺受体敏感性，COMT Val158Met基因型通过持续性操作任务的表现影响多巴胺受体敏感性。在逻辑回归分析中，两种测量方法下多巴胺受体敏感性降低均预测了酒精依赖，COMT Val158Met和DRD2 Taq1A基因型无相加效应。
COMT Val158Met和DRD2 Taq1A可能影响中枢多巴胺受体敏感性这一中间表型。COMT Val158Met和DRD2 Taq1A可能分别通过降低前额叶皮质和后脑的多巴胺受体敏感性，赋予酒精依赖风险。
