Background:Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies.Methods:We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD.Results:After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that APOB-mediated low-density lipoprotein cholesterol was associated with lower ADHD risk (odds ratio [ OR] = 0.90, 95% confidence interval [CI] [0.84, 0.97]; p = .007), whereas LPL-mediated triglycerides levels were associated with a higher risk of ADHD ( OR = 1.13, 95% CI [1.06, 1.21]; p < .001).Conclusion:Our results suggest that APOB gene and LPL gene may be candidate drug target genes for the treatment of ADHD.

中文翻译：

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脂质和降脂药物靶基因与注意力缺陷多动障碍的遗传关联

背景：脂质代谢在神经系统发育中起着至关重要的作用。胆固醇缺乏会导致多种神经发育障碍，例如自闭症谱系障碍和脆性X综合征。人们已经做出了很多努力来寻找与 ADHD 相关和致病的生物标志物，其中脂质是一种可能的病因因素，并得到了广泛的研究。我们旨在利用孟德尔随机化 (MR) 研究评估血脂特征、降脂药物和注意力缺陷多动障碍 (ADHD) 结局之间的因果关系。方法：我们使用全基因组关联研究的汇总数据来探索因果关系循环脂质相关特征与多动症之间的关系。然后，提取降脂药物靶基因表达的数量性状基因座以及与脂质性状相关的遗传变异。采用基于汇总数据的MR和反方差加权MR（IVW-MR）来研究这些药物靶基因的表达与ADHD之间的相关性。结果：经过严格筛选，最终纳入939个工具变量为单变量孟德尔随机化分析。然而，血脂状况与多动症风险之间没有相关性。IVW-MR 方法的药物靶点分析观察到 APOB 介导的低密度脂蛋白胆固醇与较低的 ADHD 风险相关（比值比 [ OR] = 0.90，95% 置信区间 [CI] [0.84, 0.97]；p = .007 ），而 LPL 介导的甘油三酯水平与 ADHD 的较高风险相关（OR = 1.13，95% CI [1.06, 1.21]；p < .001）。结论：我们的结果表明 APOB 基因和 LPL 基因可能是候选基因治疗ADHD的药物靶基因。