Sengupta Sarojini M, Grizenko Natalie, Fortier Marie-Ève, Ter-Stepanian Marina, Joober Ridha
Douglas Mental Health University Institute, Montreal, Quebec.
Department of Psychiatry, McGill University, Montreal, Quebec.
J Can Acad Child Adolesc Psychiatry. 2020 Aug;29(3):188-201. Epub 2020 Aug 1.
The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder.
We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions.
Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder.
These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.
注意缺陷多动障碍（ADHD）的病因复杂，涉及遗传和环境因素。最近的ADHD全基因组关联研究确定了12个与该疾病显著相关的基因座。然而，正如作者所强调的，这些基因座“仅占”ADHD风险的“极小一部分”。有人提出，区分以下两点可能很重要：（1）该疾病的临床复杂性，以及（2）遗传和环境因素之间的复杂相互作用，以便更好地剖析该疾病的病因。
在过去15年中，我们对一大群患有ADHD的儿童（约850个家庭）进行了一项与临床相关的药物行为遗传学研究。该研究包括对定量行为和神经心理学表型的详细评估，以及这些表型对固定剂量哌甲酯（0.5mg/kg，每日两次）治疗的短期反应。研究了特定的遗传标记和环境因素与这些维度的关联。
在此，我们展示的结果突出了检查与定量性状的遗传关联的重要性，包括那些与研究领域标准（RDoC）相关的结构。此外，我们证明，通过在根据关键环境暴露（孕期母亲吸烟或压力）分层的儿童群体中进行关联分析，我们能够提高发现参与该疾病的基因的敏感性。
这些结果表明，为了揭示该疾病“缺失的遗传度”，深度表型分析和减少异质性可能势在必行。
