Gui Jiawei, Xia Ziyi, Wan Keqi, Dong Xiangli, Sun Weiming
Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Postdoctoral Research Station, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Brain Behav. 2025 Jul;15(7):e70664. doi: 10.1002/brb3.70664.
The risk of attention-deficit/hyperactivity disorder (ADHD) may involve genetic regulation by specific brain cells in the prefrontal cortex, but the causal associations are currently unclear.
We integrated single-cell cis-expression quantitative trait loci (cis-eQTLs) from the prefrontal cortex with ADHD genome-wide association studies (GWASs). Using Mendelian randomization (MR) and Bayesian colocalization analyses, we assessed how brain cell-specific gene expression regulation affects ADHD susceptibility. We also examined the association between brain cell-type proportion and ADHD risk and used bioinformatics analyses to explore risk gene functions and identify potential drug-repurposing targets.
Single-cell eQTL MR analysis revealed that brain cell-specific gene regulation was causally linked to ADHD risk. For example, astrocyte-specific VIM expression was significantly associated with increased ADHD risk (β = 0.167, SE = 0.0388, p = 1.63 × 10⁵). Further MR analysis of ADHD subtypes revealed that certain associations exhibited stronger causal effects in childhood, late-diagnosed, or persistent ADHD. Bayesian colocalization analysis further supported 24 unique genes, including VIM in astrocytes (PPH4 = 90.8%), which showed strong evidence of shared genetic signals with ADHD. The proportions of inhibitory neurons and oligodendrocytes in the prefrontal cortex were associated with specific ADHD subtypes. Bioinformatics analyses showed that risk genes were enriched in certain brain cell types and pathways relevant to ADHD pathogenesis, aligning with MR findings.
Our results identify 24 cell-specific genes in the prefrontal cortex that may mediate ADHD risk and highlight promising molecular targets for therapeutic development.
注意力缺陷多动障碍（ADHD）的风险可能涉及前额叶皮质中特定脑细胞的基因调控，但目前因果关系尚不清楚。
我们将前额叶皮质的单细胞顺式表达定量性状位点（cis-eQTLs）与ADHD全基因组关联研究（GWASs）相结合。使用孟德尔随机化（MR）和贝叶斯共定位分析，我们评估了脑细胞特异性基因表达调控如何影响ADHD易感性。我们还研究了脑细胞类型比例与ADHD风险之间的关联，并使用生物信息学分析来探索风险基因功能并确定潜在的药物再利用靶点。
单细胞eQTL MR分析表明，脑细胞特异性基因调控与ADHD风险存在因果关系。例如，星形胶质细胞特异性波形蛋白（VIM）表达与ADHD风险增加显著相关（β = 0.167，标准误 = 0.0388，p = 1.63×10⁻⁵）。对ADHD亚型的进一步MR分析表明，某些关联在儿童期、晚发性或持续性ADHD中表现出更强的因果效应。贝叶斯共定位分析进一步支持了24个独特基因，包括星形胶质细胞中的VIM（后验概率4 = 90.8%），这些基因显示出与ADHD共享遗传信号的有力证据。前额叶皮质中抑制性神经元和少突胶质细胞的比例与特定的ADHD亚型相关。生物信息学分析表明，风险基因在与ADHD发病机制相关的某些脑细胞类型和途径中富集，与MR结果一致。
我们的研究结果确定了前额叶皮质中24个细胞特异性基因，这些基因可能介导ADHD风险，并突出了治疗开发中前景广阔的分子靶点。
