Schizophrenia Research Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, 156-8506, Tokyo, Japan.
Department of Adolescent Psychiatry, Nihonbashi Sun Clinic, 2-1-21, Nihonbashi, Chuou-ku, Tokyo, 103-0027, Japan.
Transl Psychiatry. 2021 May 28;11(1):331. doi: 10.1038/s41398-021-01460-1.
Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, were possibly affected in PEN-SCZ. To the best of our knowledge, this is the first genome-wide CNV-miRNA study suggesting the role of CNV-miRNAs in the etiology of PEN-SCZ, through effects on genes related to glycation/oxidative stress and synaptic function. Our findings provide supportive evidence that glycation/oxidative stress possibly caused by genetic defects related to the posttranscriptional modification may lead to synaptic dysfunction. Therefore, targeting miRNAs may be one of the promising approaches for the treatment of PEN-SCZ.
先前，我们鉴定出一个精神分裂症（SCZ）亚群，其血浆戊糖素水平升高，戊糖素是糖基化和氧化应激的标志物。然而，其致病的遗传因素在很大程度上仍是未知的。最近，有人提出，通过拷贝数可变 microRNAs（CNV-miRNAs）的失调翻译后修饰可能导致 SCZ 的发病机制。在这里，我们进行了整合的全基因组 CNV-miRNA 分析，以研究与累积血浆戊糖素（PEN-SCZ）相关的 SCZ 的发病机制。在 PEN-SCZ 和非 PEN-SCZ 组之间，比较了 CNV 中 miRNA 的 CNV-miRNA 数量和基因本体论（GO）。进一步对 miRNA 靶基因进行了基因集富集分析，以评估 PEN-SCZ 中受影响的途径。我们发现，miRNA 在 PEN-SCZ 与非 PEN-SCZ 组的 CNV 中显著富集（p=0.032）。值得注意的是，根据 GO 分析，两组中失调的神经发育事件可能有不同的起源。此外，miRNA 靶基因的基因集富集分析表明，涉及糖基化/氧化应激和突触神经传递，特别是谷氨酸/GABA 受体信号的 miRNA 可能在 PEN-SCZ 中受到影响。据我们所知，这是第一项全基因组 CNV-miRNA 研究，表明 CNV-miRNAs 通过对与糖基化/氧化应激和突触功能相关的基因的影响，在 PEN-SCZ 的发病机制中起作用。我们的研究结果提供了支持性证据，表明与转录后修饰相关的遗传缺陷可能导致糖基化/氧化应激，从而导致突触功能障碍。因此，针对 miRNA 可能是治疗 PEN-SCZ 的一种有前途的方法。
