Lithium has been the first-line treatment for bipolar disorder (BD) for more than six decades. Although the molecular effects of lithium have been studied extensively and gene expression changes are generally believed to be involved, the specific mechanisms of action that mediate mood regulation are still not known. In this study, a multi-step approach was used to explore the transcriptional changes that may underlie lithium's therapeutic efficacy. First, we identified genes that are associated both with lithium exposure and with BD, and second, we performed differential expression analysis of these genes in brain tissue samples from BD patients (n = 42) and healthy controls (n = 42). To identify genes that are regulated by lithium exposure, we used high-sensitivity RNA-sequencing of corpus callosum (CC) tissue samples from lithium-treated (n = 8) and non-treated (n = 9) rats. We found that lithium exposure significantly affected 1108 genes (FDR < 0.05), 702 up-regulated and 406 down-regulated. These genes were mostly enriched for molecular functions related to signal transduction, including well-established lithium-related pathways such as mTOR and Wnt signaling. To identify genes with differential expression in BD, we performed expression quantitative trait loci (eQTL) analysis on BD-associated genetic variants from the most recent genome-wide association study (GWAS) using three different gene expression databases. We found 307 unique eQTL genes regulated by BD-associated variants, of which 12 were also significantly modulated by lithium treatment in rats. Two of these showed differential expression in the CC of BD cases: RPS23 was significantly down-regulated (p = 0.0036, fc = 0.80), while GRIN2A showed suggestive evidence of down-regulation in BD (p = 0.056, fc = 0.65). Crucially, GRIN2A was also significantly up-regulated by lithium in the rat brains (p = 2.2e-5, fc = 1.6), which suggests that modulation of GRIN2A expression may be a part of the therapeutic effect of the drug. These results indicate that the recent upsurge in research on this central component of the glutamatergic system, as a target of novel therapeutic agents for affective disorders, is warranted and should be intensified.

中文翻译：

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探索双相情感障碍中锂的转录作用机制：一项多步骤研究。

锂成为双相情感障碍（BD）的一线治疗已有六十多年了。尽管已经广泛研究了锂的分子作用，并且普遍认为涉及基因表达的变化，但是介导情绪调节的具体作用机制仍然未知。在这项研究中，采用了多步骤方法来探讨可能是锂的治疗功效基础的转录变化。首先，我们确定了与锂暴露和BD相关的基因，其次，我们对BD患者（n = 42）和健康对照（n = 42）的脑组织样本中的这些基因进行了差异表达分析。为了确定受锂暴露影响的基因，我们对来自锂处理（n = 8）和未处理（n = 9）大鼠的call体（CC）组织样品进行了高灵敏度RNA测序。我们发现锂暴露显着影响了1108个基因（FDR <0.05），702个上调和406个下调。这些基因在与信号转导相关的分子功能上最丰富，包括完善的锂相关途径，例如mTOR和Wnt信号转导。为了鉴定在BD中差异表达的基因，我们使用三个不同的基因表达数据库对来自最新的全基因组关联研究（GWAS）的BD相关遗传变异进行了表达定量性状基因座（eQTL）分析。我们发现了307个受BD相关变体调控的独特eQTL基因，其中12个也受到大鼠锂处理的显着调节。其中两个在BD病例的CC中显示差异表达：RPS23显着下调（p = 0.0036，fc = 0.80），而GRIN2A显示了BD下调的暗示证据（p = 0.056，fc = 0.65）。至关重要的是，大鼠大脑中的锂也显着上调了GRIN2A（p = 2.2e-5，fc = 1.6），这表明对GRIN2A表达的调节可能是该药物治疗作用的一部分。这些结果表明，对于作为情感障碍的新型治疗剂的目标的谷氨酸能系统的这一主要组成部分的研究的最近兴起是有必要的，并且应该予以加强。锂在大鼠脑中也显着上调了GRIN2A（p = 2.2e-5，fc = 1.6），这表明对GRIN2A表达的调节可能是该药物治疗作用的一部分。这些结果表明，对于作为情感障碍的新型治疗剂的目标的谷氨酸能系统的这一主要组成部分的研究的最近兴起是有必要的，并且应该予以加强。锂在大鼠脑中也显着上调了GRIN2A（p = 2.2e-5，fc = 1.6），这表明对GRIN2A表达的调节可能是该药物治疗作用的一部分。这些结果表明，对于作为情感障碍的新型治疗剂的目标的谷氨酸能系统的这一主要组成部分的研究的最近兴起是有必要的，并且应该予以加强。