Levchenko Anastasia, Vyalova Natalia M, Nurgaliev Timur, Pozhidaev Ivan V, Simutkin German G, Bokhan Nikolay A, Ivanova Svetlana A
Theodosius Dobzhansky Center for Genome Bioinformatics, Saint Petersburg State University, Saint Petersburg, Russia.
Tomsk National Research Medical Center, Mental Health Research Institute, Russian Academy of Sciences, Tomsk, Russia.
Front Genet. 2020 Aug 25;11:936. doi: 10.3389/fgene.2020.00936. eCollection 2020.
GSK3B, BDNF, NGF, NRG1, HTR2C, and PIP4K2A play important roles in molecular mechanisms of psychiatric disorders. GSK3B occupies a central position in these molecular mechanisms and is also modulated by psychotropic drugs. BDNF regulates a number of key aspects in neurodevelopment and synaptic plasticity. NGF exerts a trophic action and is implicated in cerebral alterations associated with psychiatric disorders. NRG1 is active in neural development, synaptic plasticity, and neurotransmission. HTR2C is another important psychopharmacological target. PIP4K2A catalyzes the phosphorylation of PI5P to form PIP2, the latter being implicated in various aspects of neuronal signal transduction. In the present study, the six genes were sequenced in a cohort of 19 patients with bipolar affective disorder, 41 patients with recurrent depressive disorder, and 55 patients with depressive episode. The study revealed a number of genetic variants associated with antidepressant treatment response, time to recurrence of episodes, and depression severity. Namely, alleles of rs35641374 and rs10508649 ( and ) may be prognostic biomarkers of time to recurrence of depressive and manic/mixed episodes among patients with bipolar affective disorder. Alleles of NC_000008.11:g.32614509_32614510del, rs61731109, and rs10508649 (also and ) seem to be predictive biomarkers of response to pharmacological antidepressant treatment on the 28th day assessed by the HDRS-17 or CGI-I scale. In particular, the allele G of rs10508649 () may increase resistance to antidepressant treatment and be at the same time protective against recurrent manic/mixed episodes. These results support previous data indicating a biological link between resistance to antidepressant treatment and mania. Bioinformatic functional annotation of associated variants revealed possible impact for transcriptional regulation of . In addition, the allele A of rs2248440 () may be a prognostic biomarker of depression severity. This allele decreases expression of the neighboring immune system gene in the putamen according to the GTEx portal. The variant rs2248440 is near rs6318 (previously associated with depression and effects of psychotropic drugs) that is an eQTL for the same gene and tissue. Finally, the study points to several protein interactions relevant in the pathogenesis of mood disorders. Functional studies using cellular or animal models are warranted to support these results.
糖原合成酶激酶3β（GSK3B）、脑源性神经营养因子（BDNF）、神经生长因子（NGF）、神经调节蛋白1（NRG1）、5-羟色胺受体2C（HTR2C）和磷脂酰肌醇-4-激酶2α（PIP4K2A）在精神障碍的分子机制中发挥重要作用。GSK3B在这些分子机制中占据核心地位，并且也受到精神药物的调节。BDNF调节神经发育和突触可塑性的多个关键方面。NGF发挥营养作用，并与精神障碍相关的脑部改变有关。NRG1在神经发育、突触可塑性和神经传递中发挥作用。HTR2C是另一个重要的精神药理学靶点。PIP4K2A催化磷脂酰肌醇5磷酸（PI5P）磷酸化形成磷脂酰肌醇4,5-二磷酸（PIP2），后者参与神经元信号转导的各个方面。在本研究中，对19例双相情感障碍患者、41例复发性抑郁症患者和55例抑郁发作患者进行了这六个基因的测序。该研究揭示了一些与抗抑郁治疗反应、发作复发时间和抑郁严重程度相关的基因变异。具体而言，rs35641374和rs10508649的等位基因（和）可能是双相情感障碍患者抑郁和躁狂/混合发作复发时间的预后生物标志物。NC_000008.11:g.32614509_32614510del、rs61731109和rs10508649的等位基因（也是和）似乎是通过汉密尔顿抑郁量表-17项（HDRS-17）或临床总体印象-改善量表（CGI-I）评估的第28天对抗抑郁药物治疗反应的预测生物标志物。特别是，rs10508649的等位基因G（）可能增加对抗抑郁治疗的耐药性，同时预防复发性躁狂/混合发作。这些结果支持了先前的数据，表明抗抑郁治疗耐药性与躁狂之间存在生物学联系。相关变异的生物信息学功能注释揭示了对转录调控的可能影响。此外，rs2248440的等位基因A（）可能是抑郁严重程度的预后生物标志物。根据基因型组织表达（GTEx）数据库，该等位基因会降低壳核中邻近免疫系统基因的表达。变异rs2248440靠近rs6318（先前与抑郁症和精神药物的作用相关），rs6318是同一基因和组织的表达数量性状位点（eQTL）。最后，该研究指出了情绪障碍发病机制中几个相关的蛋白质相互作用。有必要使用细胞或动物模型进行功能研究以支持这些结果。
