BACKGROUND Mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD), have a complex etiology, and identification of underlying genetic risk factors is challenging. This study used a multistep approach to identify and validate a novel risk gene for ADHD and psychiatric comorbidity. METHODS In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copy-number variations (CNVs) linked to disease. Genes present in the identified CNV were subsequently tested for their association with ADHD in the largest data set currently available (n = 55,374); this gene-set and gene-based association analyses were based on common genetic variants. Significant findings were taken forward for functional validation using Drosophila melanogaster as biological model system, altering gene expression using the GAL4-UAS system and a pan-neuronal driver, and subsequently characterizing locomotor activity and sleep as functional readouts. RESULTS We identified a copy number gain in 8p23.3, which segregated with psychiatric phenotypes in the family and was confirmed by quantitative RT-PCR. Common genetic variants in this locus were associated with ADHD, especially those in FBXO25 and TDRP. Overexpression of the FBXO25 orthologue in two Drosophila models consistently led to increased locomotor activity and reduced sleep compared with the genetic background control. CONCLUSIONS We combine ADHD risk gene identification in an individual family with genetic association testing in a large case-control data set and functional validation in a model system, together providing an important illustration of an integrative approach suggesting that FBXO25 contributes to key features of ADHD and comorbid neuropsychiatric disorders.

中文翻译：

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从人到苍蝇——汇聚证据将 FBXO25 与 ADHD 和共病精神表型联系起来。


背景精神障碍，包括注意力缺陷/多动障碍（ADHD），具有复杂的病因学，并且识别潜在的遗传风险因素具有挑战性。这项研究采用多步骤方法来识别和验证 ADHD 和精神共病的新风险基因。方法 在一个受到 ADHD 和并发疾病严重影响的家庭中，我们应用单核苷酸多态性 (SNP) 阵列分析来检测与疾病相关的拷贝数变异 (CNV)。随后在目前可用的最大数据集中（n = 55,374）测试了已识别的 CNV 中存在的基因与 ADHD 的关联；这种基因组和基于基因的关联分析是基于常见的遗传变异。使用果蝇作为生物模型系统，使用 GAL4-UAS 系统和泛神经元驱动程序改变基因表达，并随后将运动活动和睡眠表征为功能读数，从而进行了功能验证。结果我们在 8p23.3 中发现了拷贝数增加，该拷贝数与家族中的精神表型分离，并通过定量 RT-PCR 得到了证实。该位点的常见遗传变异与 ADHD 相关，尤其是 FBXO25 和 TDRP 中的变异。与遗传背景对照相比，FBXO25 直系同源物在两个果蝇模型中的过度表达始终导致运动活动增加和睡眠减少。 结论 我们将单个家族中 ADHD 风险基因的识别与大型病例对照数据集中的遗传关联测试以及模型系统中的功能验证相结合，共同提供了一个综合方法的重要说明，表明 FBXO25 有助于 ADHD 的关键特征和共病神经精神疾病。