Impaired executive inhibition is a core deficit of attention deficit hyperactivity disorder (ADHD), which is a common childhood-onset psychiatric disorder with high heritability. In this study, we performed a two-stage genome-wide association study of executive inhibition in ADHD in Han Chinese. We used the Stroop color-word interference test to evaluate executive inhibition. After quality control, 780 samples with phenotype and covariate data were included in the discovery stage, whereas 922 samples were included in the replication stage. We identified one new significant locus at 7p22.3 for the Stroop word interference time (rs11514810, P=3.42E-09 for discovery, P=0.01176 for replication and combined P=5.249E-09). Regulatory feature analysis and expression quantitative trait loci (eQTL) data showed that this locus contributes to MICALL2 expression in the human brain. Most genes in the network interacting with MICALL2 were associated with psychiatric disorders. Furthermore, hyperactive-impulsive-like behavior was induced by reducing the expression of the zebrafish gene that is homologous to MICALL2, which could be rescued by tomoxetine (atomoxetine), a clinical medication for ADHD. Our results suggested that MICALL2 is a new susceptibility gene for executive inhibition deficiency related to hyperactive-impulsive behavior in ADHD, further emphasizing the possible role of neurodevelopmental genes in the pathogenic mechanism of ADHD.

中文翻译：

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确定了一种新的调控MICALL2表达的基因座，与注意力缺陷多动障碍儿童的执行抑制相关。

执行抑制力受损是注意力缺陷多动障碍（ADHD）的核心缺陷，注意力缺陷多动障碍是一种常见的儿童期精神疾病，遗传性高。在这项研究中，我们进行了两阶段全基因组关联研究，研究汉族人多动症的执行抑制作用。我们使用Stroop颜色词干扰测试来评估执行抑制。在质量控制后，发现阶段包括780个具有表型和协变量数据的样本，而复制阶段包括922个样本。我们在Stroop字干扰时间中找到了7p22.3处的一个新的重要基因座（rs11514810，发现时P = 3.42E-09，复制时P = 0.01176，合并后的P = 5.249E-09）。监管特征分析和表达数量性状基因座（eQTL）数据表明，该基因座有助于人脑中MICALL2的表达。网络中与MICALL2相互作用的大多数基因都与精神疾病有关。此外，通过减少与MICALL2同源的斑马鱼基因的表达，诱导了类似冲动的行为，这可以通过多莫西汀（atomoxetine）（一种多动症的临床药物）来挽救。我们的结果表明，MICALL2是与多动症多动性行为相关的执行抑制缺陷的新易感基因，进一步强调了神经发育基因在多动症的致病机制中的可能作用。通过减少与MICALL2同源的斑马鱼基因的表达，诱导出类似冲动的行为，这可以通过多莫西汀（托莫西汀）（一种多动症的临床药物）来挽救。我们的研究结果表明，MICALL2是与多动症多动冲动行为有关的执行抑制缺陷的新易感基因，进一步强调了神经发育基因在多动症的致病机制中的可能作用。通过减少与MICALL2同源的斑马鱼基因的表达，诱导出类似冲动的行为，这可以通过多莫西汀（托莫西汀）（一种多动症的临床药物）来挽救。我们的研究结果表明，MICALL2是与多动症多动冲动行为有关的执行抑制缺陷的新易感基因，进一步强调了神经发育基因在多动症的致病机制中的可能作用。