Douglas Mental Health University Institute, Montreal, QC, Canada.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Neuromolecular Med. 2018 Dec;20(4):515-524. doi: 10.1007/s12017-018-8504-z. Epub 2018 Jul 26.
Results of candidate gene investigations in ADHD have been difficult to replicate. The complexity of the phenotypes and their underlying determinants, and the relatively small effect sizes of genetic variants may, in part, be contributing to these inconsistencies. The objective of this study is to conduct an exploratory analysis using a comprehensive approach to investigate the role of candidate genes. This approach combines a dimensional behavioural approach akin to Research Domain Criteria (RDoC), a pharmaco-dynamic evaluation of behaviours relevant to ADHD, together with association and linkage testing in a large sample of children with ADHD. Parents, teachers, and research staff evaluated children with ADHD under three experimental conditions (EC): 1 week of baseline observation, followed by 1 week of methylphenidate (MPH) and 1 week of placebo, administered in a double-blind crossover order. Several quantitative behavioural and cognitive dimensions relevant for ADHD were also assessed. We combined family-based (FBAT) and quantitative trait genetic analyses (n = 575 probands with members of their nuclear families) to investigate the role of DRD3 (Ser-9-Gly) in ADHD and its relevant behavioural dimensions. Comparing the behaviours of children with different genotypes under the three EC showed a nominal association between the T allele and poorer behavioural scores during the MPH week (as assessed by teachers), particularly in boys. With the family-based analysis, the T allele showed a nominal association with increased risk for ADHD, response to placebo and MPH as assessed by research staff, and the modulation of other behavioural and cognitive dimensions. These results provide convergent, albeit preliminary evidence for the implication of the DRD3 (Ser-9-Gly) polymorphism in the aetiology of ADHD and the modulation of its various behavioural dimensions, including RDoC cognitive constructs and response to pharmacological probes. This illustrative example suggests that this research paradigm might help to reliably uncover the role of other candidate genes in ADHD.
候选基因在 ADHD 中的研究结果一直难以复制。表型的复杂性及其潜在决定因素，以及遗传变异的相对较小效应大小，可能在一定程度上导致了这些不一致。本研究的目的是采用综合方法进行探索性分析，以研究候选基因的作用。这种方法结合了类似于研究领域标准（RDoC）的维度行为方法、对与 ADHD 相关行为的药物动力学评估，以及在 ADHD 儿童的大样本中进行的关联和连锁测试。父母、教师和研究人员在三种实验条件（EC）下评估 ADHD 儿童：1 周的基线观察期，随后是 1 周的哌醋甲酯（MPH）和 1 周的安慰剂，以双盲交叉顺序给药。还评估了几个与 ADHD 相关的定量行为和认知维度。我们结合基于家庭的（FBAT）和定量性状遗传分析（n=575 名先证者及其核心家庭成员），研究 DRD3（Ser-9-Gly）在 ADHD 及其相关行为维度中的作用。比较具有不同基因型的儿童在三种 EC 下的行为表现表明，T 等位基因与 MPH 周期间（由教师评估）较差的行为评分之间存在名义关联，特别是在男孩中。通过基于家庭的分析，T 等位基因与 ADHD、研究人员评估的安慰剂和 MPH 反应的风险增加以及其他行为和认知维度的调节呈名义关联。这些结果提供了一致的、尽管是初步的证据，表明 DRD3（Ser-9-Gly）多态性与 ADHD 的病因学以及其各种行为维度的调节有关，包括 RDoC 认知结构和对药理学探针的反应。这个说明性的例子表明，这种研究范式可能有助于可靠地揭示其他候选基因在 ADHD 中的作用。
