Objective:

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster.

Methods:

Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits.

Results:

The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype.

Conclusions:

This study reveals that a large set of intellectual disability–related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.

中文翻译：

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智力障碍相关基因对果蝇多动症风险和运动能力的贡献。

目的：

注意缺陷多动障碍（ADHD）是一种常见的高度遗传性神经精神病。多动症常常与智力障碍并发，并且已经提出了共享的重叠遗传学。这项研究的目的是通过研究携带与智力障碍相关的罕见突变的基因是否通过常见的遗传变异而导致ADHD风险，从而确定新的ADHD基因。验证和表征候选人使用果蝇。

方法：

使用来自精神病基因组学协会的ADHD荟萃分析数据（N = 19,210）和ADHD，通过基因集和全基因分析，测试了396个常染色体智力残疾基因的诊断基因组中的常见遗传变异与ADHD风险的相关性伦贝克综合精神病学研究计划的数据用于复制（N = 37,076）。在果蝇中，通过评估运动能力和大脑回路中那些基因敲低后的睡眠来对重要基因进行功能验证和表征。

结果：

在发现和复制数据集中，智障基因组与ADHD风险显着相关。最一致相关的三个基因是MEF2C，ST3GAL3和TRAPPC9。作者对果蝇的两个进化保守基因进行了功能鉴定，发现它们在多巴胺能（dMEF2）和昼夜节律神经元（dTRAPPC9）中的敲低导致运动能力增强和睡眠减少，与人类表型一致。

结论：

这项研究表明，大量与智力障碍相关的基因通过常见等位基因的作用导致多动症风险。利用这种连续性，作者将TRAPPC9，MEF2C和ST3GAL3鉴定为新的ADHD候选基因。果蝇中的特征表明TRAPPC9和MEF2C通过不同的神经底物促成ADHD相关行为。