Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes

Anand, Amit; McClintick, Jeanette N.; Murrell, Jill R.; Karne, Harish; Nürnberger, John I.; Edenberg, Howard J.

doi:10.1159/000446348

Cited by 29 publications

(35 citation statements)

References 29 publications

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“…In the final biomarker panel, we also found a trend for an increase in IL5RA expression in BD ( p value for BD = 0.056; fold change 1.16); however, IL5RA expression in SZ was significantly decreased and passing the FDR ( p value for SZ vs. NC = 2.65E–08; fold change –1.59). Regarding PLB1 (phospholipase B1) in PBMCs, lithium decreased its expression (–1.17 fold change), passing the FDR [87] in PBMCs, while in the present study, PLB1 was significantly decreased in BD by –1.19 and was not significantly increased in SZ ( p = 0.06; fold change 1.16). It is unlikely that some expression in the biomarker panel might be due to lithium treatment, since only 2 BD subjects were lithium treated in this study.…”

Section: Discussioncontrasting

confidence: 49%

“…For example, there was a consistent increase in expression of IL5RA (interleukin 5 receptor, alpha) in lithium-treated subjects with BD in PBMCs that passed a strict FDR [87]. In the final biomarker panel, we also found a trend for an increase in IL5RA expression in BD ( p value for BD = 0.056; fold change 1.16); however, IL5RA expression in SZ was significantly decreased and passing the FDR ( p value for SZ vs. NC = 2.65E–08; fold change –1.59).…”

Section: Discussionmentioning

confidence: 99%

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Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

et al. 2017

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This study developed potential blood-based biomarker tests for diagnosing and differentiating schizophrenia (SZ), bipolar disorder type I (BD), and normal control (NC) subjects using mRNA gene expression signatures. A total of 90 subjects (n = 30 each for the three groups of subjects) provided blood samples at two visits. The Affymetrix exon microarray was used to profile the expression of over 1.4 million probesets. We selected potential biomarker panels using the temporal stability of the probesets and also back-tested them at two different visits for each subject. The 18-gene biomarker panels, using logistic regression modeling, correctly differentiated the three groups of subjects with high accuracy across the two different clinical visits (83–88% accuracy). The results are also consistent with the actual data and the “leave-one-out” analyses, indicating that the models should be predictive when applied to independent data cohorts. Many of the SZ and BD subjects were taking antipsychotic and mood stabilizer medications at the time of blood draw, raising the possibility that these drugs could have affected some of the differential transcription signatures. Using an independent Illumina data set of gene expression data from antipsychotic medication-free SZ subjects, the 18-gene biomarker panels produced a receiver operating characteristic curve accuracy greater than 0.866 in patients that were less than 30 years of age and medication free. We confirmed select transcripts by quantitative PCR and the nCounter® System. The episodic nature of psychiatric disorders might lead to highly variable results depending on when blood is collected in relation to the severity of the disease/symptoms. We have found stable trait gene panel markers for lifelong psychiatric disorders that may have diagnostic utility in younger undiagnosed subjects where there is a critical unmet need. The study requires replication in subjects for ultimate proof of the utility of the differential diagnosis.

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

et al. 2017

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“…Few such studies to date have been undertaken using patient samples but rather cultured cells that have undergone immortalisation 30–32 . Results so far have implicated, for example, apoptotic pathways 30,31 , neutral amino acid transport 30 , protein ubiquitination, and protein synthesis 32 .…”

Section: Introductionmentioning

confidence: 99%

A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder

et al. 2018

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Lithium is the first-line treatment for bipolar affective disorder (BPAD) but two-thirds of patients respond only partially or not at all. The reasons for this high variability in lithium response are not well understood. Transcriptome-wide profiling, which tests the interface between genes and the environment, represents a viable means of exploring the molecular mechanisms underlying lithium response variability. Thus, in the present study we performed co-expression network analyses of whole-blood-derived RNA-seq data from n = 50 lithium-treated BPAD patients. Lithium response was assessed using the well-validated ALDA scale, which we used to define both a continuous and a dichotomous measure. We identified a nominally significant correlation between a co-expression module comprising 46 genes and lithium response represented as a continuous (i.e., scale ranging 0–10) phenotype (cor = −0.299, p = 0.035). Forty-three of these 46 genes had reduced mRNA expression levels in better lithium responders relative to poorer responders, and the central regulators of this module were all mitochondrially-encoded (MT-ND1, MT-ATP6, MT-CYB). Accordingly, enrichment analyses indicated that genes involved in mitochondrial functioning were heavily over-represented in this module, specifically highlighting the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) as affected processes. Disrupted ETC and OXPHOS activity have previously been implicated in the pathophysiology of BPAD. Our data adds to previous evidence suggesting that a normalisation of these processes could be central to lithium’s mode of action, and could underlie a favourable therapeutic response.

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“…Although none of these studies has the same design as ours, we did find a significant overlap between our 976 lithium-use DEGs and the lists from two studies. In the first study 18 , DEGs were detected by comparing peripheral monocyte gene expression in subjects before and after lithium monotherapy. Of the 35 DEGs discovered, 18 were shared with the current study (hypergeometric odd ratio (OR) = 13.57, P = 4.66 x 10 -12 ), and all 18 were concordant in direction (Figure S2A).…”

Section: Resultsmentioning

confidence: 99%

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

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et al. 2018

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23Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and 24 poorly understood etiology. We performed a whole blood transcriptome analysis in a BD case-25 control sample (Nsubjects = 480) by RNA sequencing. While we observed widespread differential 26 gene expression patterns between affected and unaffected individuals, these effects were largely 27 linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD 28 diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell 29 signaling and immune response functional annotations, among others, and were associated with 30 neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered 31 expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression 32 genetic risk based on information from genome-wide association studies, nor was gene 33 expression associated with polygenic risk scores for BD. Our findings suggest that BD is 34 associated with minimal changes in whole blood gene expression independent of medication use 35 but underline the importance of accounting for medication use and cell type heterogeneity in 36 psychiatric transcriptomic studies. The results of our study add to mounting evidence of lithium's 37 cell signaling and immune-related mechanisms. 38 39 strategy for uncovering disease mechanisms. Many such studies have been carried out for BD, 48and in Table 1 we present a summary that reveals a lack of consistency between findings likely 49 owing to clinical heterogeneity, differing study designs, and the low numbers of samples 50 investigated (N ≤ 62 BD subjects) . Moreover, there are many potential confounds that impact 51 gene expression, including medication. 52 Therefore, to explore gene expression changes associated with BD, we generated RNA 53 sequencing data from peripheral whole blood collected in a large, well-characterized case-control 54 cohort from The Netherlands. We examined gene expression differences between groups both at 55 the individual gene level and at the level of gene co-expression. Upon correction for technical and 56 biological variables including the use of lithium, the most widely used prescription drug in our 57 cohort, gene expression differences between subjects with BD and controls were minor. 58Differences in subjects being treated with lithium compared to those who are not, however, were 59 widespread. These differences were partially but not entirely explained by differences in cell-type 60 composition, driven by elevated neutrophil proportions in lithium users. The lithium-associated 61 changes in gene expression were independent of psychiatric genetic risk, though. Our results 62 suggest nominal BD-related gene expression effects in blood but numerous effects related to 63 lithium treatment. This work highlights the importance of accounting for medication use in 64 psychiatric transcriptomic studies and provides insight into lithium's mole...

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Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes

Cited by 29 publications

References 29 publications

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

A gene co-expression module implicating the mitochondrial electron transport chain is associated with long-term response to lithium treatment in bipolar affective disorder

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect

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