Department of Biostatistics, State Key Laboratory of Organ Failure Research, Ministry of Education, and Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
Brief Bioinform. 2024 Sep 23;25(6). doi: 10.1093/bib/bbae502.
Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disease that often affects a patient's whole life. Research has found that genetics plays an important role in the development of ADHD. However, there is still a lack of knowledge about the tissue-specific causal effects of biological processes beyond gene expression, such as alternative splicing (AS) and DNA methylation (DNAm), on ADHD. In this paper, a multi-omics study was conducted to investigate the causal effects of the transcription and the DNAm on ADHD, by integrating ADHD genome-wide association data with quantitative trait loci data of gene expression, AS, and DNAm across 14 different brain tissues. The causal effects were estimated using four different two-sample Mendelian randomization methods. Finally, we also prioritized the expression of 866 genes showing significant causal effects, including COMMD5, ENSG00000271904, HYAL3, etc., within at least one brain tissue. We prioritized 966 unique genes that have statistically significant causal AS events, within at least one of the 14 different brain tissues. These genes include PPP1R16A, GGT7, TREM2, etc. Furthermore, through mediation analysis, 106 regulatory pathways were inferred where DNAm influences ADHD through gene expression or AS processes. Our research findings provide guidance for future experimental studies on the molecular mechanisms of ADHD development, and also put forward valuable knowledge for the prevention, diagnosis, and treatment of ADHD.
注意缺陷多动障碍（ADHD）是一种慢性精神疾病，通常会影响患者的一生。研究发现，遗传在 ADHD 的发展中起着重要作用。然而，对于基因表达以外的生物过程（如选择性剪接（AS）和 DNA 甲基化（DNAm））对 ADHD 的组织特异性因果效应，我们仍然知之甚少。在本文中，我们进行了一项多组学研究，通过整合 ADHD 全基因组关联数据与横跨 14 种不同脑组织的基因表达、AS 和 DNAm 的数量性状基因座数据，研究了转录和 DNAm 对 ADHD 的因果效应。使用四种不同的两样本 Mendelian 随机化方法估计了因果效应。最后，我们还对至少一种脑组织中显示出显著因果效应的 866 个基因的表达进行了优先级排序，包括 COMMD5、ENSG00000271904、HYAL3 等。我们还对至少在 14 种不同脑组织中的一种组织中具有统计学意义的因果 AS 事件的 966 个独特基因进行了优先级排序，这些基因包括 PPP1R16A、GGT7、TREM2 等。此外，通过中介分析，推断出 106 个调控途径，其中 DNAm 通过基因表达或 AS 过程影响 ADHD。我们的研究结果为 ADHD 发展的分子机制的未来实验研究提供了指导，也为 ADHD 的预防、诊断和治疗提供了有价值的知识。
