Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

Fries, Gabriel R.; Colpo, Gabriela Delevati; Monroy-Jaramillo, Nancy; Zhao, Junfei; Zhao, Zhongming; Arnold, Jodi Gonzalez; Bowden, Charles L.; Walss‐Bass, Consuelo

doi:10.1016/j.euroneuro.2017.09.003

Cited by 16 publications

(17 citation statements)

References 68 publications

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“…Lymphoblastoid cell lines (LCLs) can be studied under controlled conditions, and have been used for functional studies that cannot be done with post-mortem brain tissue, such as identifying lithium induced gene expression changes in bipolar patients and controls (Fries et al, 2017). Recent studies have shown strong correlations between blood and brain for cis expression QTLs (eQTLs) and methylation QTLs (Qi et al, 2018).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Ethanol activates immune response in lymphoblastoid cells

McClintick

Tischfield

Deng

et al. 2019

Alcohol

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The short-term effects of alcohol on gene expression in brain tissue cannot directly be studied in humans. Because neuroimmune signaling is altered by alcohol, immune cells are a logical, accessible choice to study and might provide biomarkers. RNAseq was used to study the effects of 48 h exposure to ethanol on lymphoblastoid cell lines (LCLs) from 20 alcoholics and 20 controls. Ethanol exposure resulted in differential expression of 4,456 of the 12,503 genes detectably expressed in the LCLs (FDR ≤ 0.05); 52% of these showed increased expression. Cells from alcoholics and controls responded similarly. The genes whose expression changed fell into many pathways: NFκB, neuroinflammation, IL6, IL2, IL8, and dendritic cell maturation pathways were activated, consistent with increased signaling by NFκB, TNF, IL1, IL4, IL18, TLR4, and LPS. Signaling by Interferons A and B decreased, as did EIF2 signaling, phospholipase C signaling and Glycolysis. Baseline gene expression patterns were similar in LCLs from alcoholics and controls. At relaxed stringency (p<0.05), 465 genes differed, 230 of which were also affected by ethanol. There was a suggestion of compensation because baseline differences (no ethanol) were in the opposite direction of differences due to ethanol exposure in 78% of these genes. Pathways with IL8, phospholipase C, and α-adrenergic signaling were significant. The pattern of expression was consistent with increased signaling by several cytokines including interferons, TLR2 and TLR3 in alcoholics. Expression of genes in the cholesterol biosynthesis pathway, including the ratelimiting enzyme HMGCR, was lower in alcoholics. LCLs show many effects of ethanol exposure, some of which might provide biomarkers for alcohol use disorders. Identifying genes and pathways altered by ethanol can aid in interpreting

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Section: Accepted Manuscriptmentioning

confidence: 99%

Ethanol activates immune response in lymphoblastoid cells

McClintick

Tischfield

Deng

et al. 2019

Alcohol

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“…To relate our results to previous lithium findings, we compared the full set of DGE and DTE-only genes (n = 1108) with a set of genes associated with lithium in 18 previous transcriptomic reports [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] identified through a systematic literature search (Supplementary Materials and Methods). We found overlap with 112 genes (10.1%), many of them having similar direction and magnitude of effect (Table S3).…”

Section: Comparison Between Identified Genes and Previous Findingsmentioning

confidence: 99%

Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study

Akkouh

Skrede

Holmgren

et al. 2019

Neuropsychopharmacol.

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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 highsensitivity 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.

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“…This activation is thought to occur, at least in part, through the phosphatidylinositol 3-kinase (PI3K) pathway, as Li exposure increases PI3K/Akt1 anti-apoptotic activity and inhibition of PI3K blocks the neurotrophic effects of Li. Our recent study evaluating Li-induced gene expression alterations in lymphoblastoid cell lines (LCL) from BD patients and controls supports a role for PI3K/Akt and anti-apoptotic pathways in Li mechanisms of action [1]. While treatment in LCLs from controls did not lead to any significant differences, Li altered the expression of 236 genes in cells from patients.…”

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confidence: 86%