Laboratório de Psiquiatria Molecular-Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-903, Brazil.
Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Neurobiol. 2020 Mar;57(3):1305-1316. doi: 10.1007/s12035-019-01815-2. Epub 2019 Nov 14.
Despite the strong genetic component of psychiatric disorders, traditional genetic studies have failed to find individual genes of large effect size. Thus, alternative methods, using bioinformatics, have been proposed to solve these biological puzzles. Of these, here we employ systems biology-based approaches to identify potential master regulators (MRs) of bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD), their association with biological processes and their capacity to differentiate disorders' phenotypes. High-throughput gene expression data was used to reconstruct standard human dorsolateral prefrontal cortex regulatory transcriptional network, which was then queried for regulatory units and MRs associated with the psychiatric disorders of interest. Furthermore, the activity status (active or repressed) of MR candidates was obtained and used in cluster analysis to characterize disease phenotypes. Finally, we explored the biological processes modulated by the MRs using functional enrichment analysis. Thirty-one, thirty-four, and fifteen MR candidates were identified in BD, SZ, and MDD, respectively. The activity state of these MRs grouped the illnesses in three clusters: MDD only, mostly BD, and a third one with BD and SZ. While BD and SZ share several biological processes related to ion transport and homeostasis, synapse, and immune function, SZ showed peculiar enrichment of processes related to cytoskeleton and neuronal structure. Meanwhile, MDD presented mostly processes related to glial development and fatty acid metabolism. Our findings suggest notable differences in functional enrichment between MDD and BD/SZ. Furthermore, similarities between BD and SZ may impose particular challenges in attempts to discriminate these pathologies based solely on their transcriptional profiles. Nevertheless, we believe that systems-oriented approaches are promising strategies to unravel the pathophysiology peculiarities underlying mental illnesses and reveal therapeutic targets.
尽管精神障碍有很强的遗传成分，但传统的遗传研究未能发现具有较大效应大小的个体基因。因此，已经提出了使用生物信息学的替代方法来解决这些生物学难题。在这些方法中，我们采用基于系统生物学的方法来识别双相情感障碍（BD）、精神分裂症（SZ）和重度抑郁症（MDD）的潜在主调控因子（MRs），它们与生物学过程的关联及其区分疾病表型的能力。使用高通量基因表达数据来重建标准的人类背外侧前额叶皮层调控转录网络，然后查询与感兴趣的精神障碍相关的调控单元和 MRs。此外，还获得了 MR 候选物的活性状态（激活或抑制），并将其用于聚类分析以表征疾病表型。最后，我们使用功能富集分析探索了由 MRs 调节的生物学过程。在 BD、SZ 和 MDD 中分别鉴定出 31、34 和 15 个 MR 候选物。这些 MR 候选物的活性状态将这些疾病分为三组：仅 MDD、主要是 BD 和第三个包含 BD 和 SZ。虽然 BD 和 SZ 共享与离子转运和稳态、突触和免疫功能相关的几个生物学过程，但 SZ 表现出与细胞骨架和神经元结构相关的过程的特殊富集。同时，MDD 主要呈现与神经胶质发育和脂肪酸代谢相关的过程。我们的研究结果表明，MDD 和 BD/SZ 之间的功能富集存在显著差异。此外，BD 和 SZ 之间的相似性可能会对仅根据转录谱来区分这些病理带来特殊挑战。然而，我们相信，面向系统的方法是揭示精神疾病背后的病理生理学特征并揭示治疗靶点的有前途的策略。
