The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

Ky, Lee; Ym, Ahn; Joo, EJ; Chang, Jan‐Gowth; Ys, Kim

doi:10.1038/sj.mp.4001807

Cited by 17 publications

(15 citation statements)

References 11 publications

(11 reference statements)

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“…Interestingly, CRH (corticotrophin releasing hormone) [72,73], another key gene underlying cortisol action, was identified as differentially expressed in the analysis of PFC. Several other notable candidate genes for mood disorders were implicated in the current analyses, including DUSP6 (dual-specificity phosphatase 6) [74-76], NPY (neuropeptide Y), NR4A2 (nuclear receptor subfamily 4, group A, member 2), SST (somatastatin), GRIK2 (glutamate receptor ionotropic kainate 2 isoform precursor) [77-79], S100B (S100 calcium binding protein B) [80,81] and CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit). Perhaps of greatest interest among these is CACNA1C , which has emerged from recent genome-wide association studies as one of the leading candidate genes for bipolar disorder [82,83].…”

Section: Discussionmentioning

confidence: 99%

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Systematic review of genome-wide gene expression studies of bipolar disorder

Seifuddin¹,

Pirooznia²,

Judy³

et al. 2013

BMC Psychiatry

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BackgroundNumerous genome-wide gene expression studies of bipolar disorder (BP) have been carried out. These studies are heterogeneous, underpowered and use overlapping samples. We conducted a systematic review of these studies to synthesize the current findings.MethodsWe identified all genome-wide gene expression studies on BP in humans. We then carried out a quantitative mega-analysis of studies done with post-mortem brain tissue. We obtained raw data from each study and used standardized procedures to process and analyze the data. We then combined the data and conducted three separate mega-analyses on samples from 1) any region of the brain (9 studies); 2) the prefrontal cortex (PFC) (6 studies); and 3) the hippocampus (2 studies). To minimize heterogeneity across studies, we focused primarily on the most numerous, recent and comprehensive studies.ResultsA total of 30 genome-wide gene expression studies of BP done with blood or brain tissue were identified. We included 10 studies with data on 211 microarrays on 57 unique BP cases and 229 microarrays on 60 unique controls in the quantitative mega-analysis. A total of 382 genes were identified as significantly differentially expressed by the three analyses. Eleven genes survived correction for multiple testing with a q-value < 0.05 in the PFC. Among these were FKBP5 and WFS1, which have been previously implicated in mood disorders. Pathway analyses suggested a role for metallothionein proteins, MAP Kinase phosphotases, and neuropeptides.ConclusionWe provided an up-to-date summary of results from gene expression studies of the brain in BP. Our analyses focused on the highest quality data available and provided results by brain region so that similarities and differences can be examined relative to disease status. The results are available for closer inspection on-line at Metamoodics [http://metamoodics.igm.jhmi.edu/], where investigators can look up any genes of interest and view the current results in their genomic context and in relation to leading findings from other genomic experiments in bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

“…One of the key genes in the pathway identified by our current analysis was DUSP6, which was found to be significantly down-regulated in BP. DUSP6 is known to bind to and inactivate ERK1 and ERK2 [91], and previous studies have suggested a genetic association between DUSP6 and both schizophrenia and BP [74,75]. …”

Section: Discussionmentioning

confidence: 99%

Systematic review of genome-wide gene expression studies of bipolar disorder

Seifuddin¹,

Pirooznia²,

Judy³

et al. 2013

BMC Psychiatry

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“…ERK1/2 signaling is terminated by MAP-kinase phosphatases (MKP) encoded by members of the DUSP family of genes. DUSP6 (MKP-3) has been associated with BD in genetic (Kim et al, 2012;Lee et al, 2006) and gene expression studies, suggesting that it may be linked to the pathophysiology of BD. Most MKPs inhibit multiple protein kinases including P38, JNK, and ERK, making their effects widespread and non-specific (Kondoh and Nishida, 2007).…”

Section: Dusp6 Knockdown Potentiates Erkmentioning

confidence: 99%

“…Animal studies suggest that lithium may engage ERK as well to alter Per2 expression by activating the transcription factor EGR-1 (Kim et al, 2013). Importantly, both ERK1/2, and DUSP6, a negative regulator of ERK1/2, have been implicated in BD (Kim et al, 2012;Lee et al, 2006;. Therefore, ERK signaling may be important for understanding circadian rhythm abnormalities in BD as they pertain to lithium.…”

Section: Introductionmentioning

confidence: 99%

Disinhibition of the extracellular-signal-regulated kinase restores the amplification of circadian rhythms by lithium in cells from bipolar disorder patients

McCarthy

Wei

Landgraf

et al. 2016

European Neuropsychopharmacology

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ABSTRACT:Bipolar disorder (BD) is characterized by depression, mania, and circadian rhythm abnormalities. Lithium, a treatment for BD stabilizes mood and increases circadian rhythm amplitude. However, in fibroblasts grown from BD patients, lithium has weak effects on rhythm amplitude compared to healthy controls. To understand the mechanism by which lithium differentially affects rhythm amplitude in BD cells, we investigated the extracellular-signal-regulated kinase (ERK) and related signaling molecules linked to BD and circadian rhythms. In fibroblasts from BD patients, controls and mice, we assessed the contribution of the ERK pathway to lithium-induced circadian rhythm amplification. Protein analyses revealed low phospho-ERK1/2 content in fibroblasts from BD patients vs. controls. Pharmacological inhibition of ERK1/2 by PD98059 attenuated the rhythm amplification effect of lithium, while inhibition of two related kinases, c-Jun N-terminal kinase (JNK), and P38 did not. Knockdown of the transcription factors CREB and EGR-1, downstream effectors of ERK1/2, reduced baseline rhythm amplitude, but did not alter rhythm amplification by lithium. In contrast, ELK-1 knockdown amplified rhythms, an effect that was not increased further by the addition of lithium, suggesting this transcription factor may regulate the effect of lithium on amplitude. Augmentation of ERK1/2 signaling through DUSP6 knockdown sensitized NIH3T3 cells to rhythm amplification by lithium. In BD fibroblasts, DUSP6 knockdown reversed the BD rhythm phenotype, restoring the ability of lithium to increase amplitude in these cells. We conclude that the inability of lithium to regulate circadian rhythms in BD may reflect reduced ERK activity, and signaling through ELK-1.

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“…Electroconvulsive seizure induces alterations in dusp6 expression in rat brain related to changes in ERK pathway (Kodama et al, 2005). We have reported the genetic association between DUSP6 gene and bipolar disorder (Kim et al, 2012;Lee et al, 2006). Among the associated single nucleotide polymorphisms (SNPs), rs808820 is located on intron 1, and the A/G polymorphism in this SNP [5′-CAATC(A/G)TCTAA-3′] is associated with alteration in the sequence from CA to CG, which can add a CpG site for methylation (Kim et al, 2012).…”

Section: Discussionmentioning

confidence: 98%