School of Biological Sciences, Faculty of Science, Monash University, Clayton, Australia.
Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, Australia.
Transl Psychiatry. 2020 Nov 6;10(1):385. doi: 10.1038/s41398-020-01077-w.
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7 fish showed comparable reductions in mRNA levels to individuals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7, but this effect did not persist into juvenile and adulthood stages. In addition, chmp7 fish had significantly smaller total brain volumes than chmp7 fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.
注意缺陷多动障碍（ADHD）是一种具有强烈遗传成分的儿童神经发育障碍。尽管 ADHD 风险基因座的定位取得了成功，但很少有工作致力于实验验证这些基因座对 ADHD 表型的贡献。ADHD 四项全基因组关联研究的荟萃分析表明 CHMP7 是 ADHD 的易感基因。映射到 CHMP7 的 DNA 变体（rs2294123）已通过生物信息学分析显示出很高的功能可能性，并与转录水平降低相关。我们使用 CRISPR-Cas9 基因组编辑生成了一个用于 ADHD 的 chmp7 斑马鱼模型。chmp7 鱼的 mRNA 水平与 CHMP7 ADHD 风险等位基因纯合子个体相当，显示出明显的减少。与 chmp7 相比，这些鱼在受精后 6 天的 24 小时内表现出明显的过度活跃，但这种影响不会持续到幼体和成年阶段。此外，chmp7 鱼的总脑体积明显小于 chmp7 鱼。最后，通过应用哌醋甲酯（ADHD 的主要药物治疗方法），受精后 6 天的过度活跃显著降低。总体而言，这项研究强调了 CHMP7 在 ADHD 神经发育中的重要作用，并展示了斑马鱼在模拟赋予 ADHD 风险的基因的功能效应方面的实用性。
