Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Sun, Xiujun; Young, L. Trevor; Wang, Junfeng; Grof, Paul; Turecki, Gustavo; Rouleau, Guy A.; Alda, Martin

doi:10.1038/sj.npp.1300383

Cited by 46 publications

(23 citation statements)

References 44 publications

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“…[131][132][133][134] In addition to the studies of PDE4s in brain, PDE4 expression is modulated by lithium in lymphoblastoid cell lines derived from lithium-responsive patients with bipolar disorder. 135 These effects may be interpreted as meaning that the PDE4s participate in responses to therapeutic treatments, or alternatively, as providing further confirmation of PDE4 involvement in causing illness. Nicotine has also been shown to influence brain expression of PDE4s, causing dose-dependent decreases in the hippocampus, PFC and nucleus accumbens.…”

Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…22,23 The effect of lithium on gene expression was also investigated in immortalized lymphocytes from bipolar disorder patients. 24 However, only a few microarray analysis using immortalized lymphocytes from patients with schizophrenia have been reported. [25][26][27] Whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

et al. 2011

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The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes. Journal of Human Genetics INTRODUCTIONSchizophrenia is a complex genetic disorder that is characterized by profound disturbances of cognition, emotion and social functioning. It affects B1% of the general population world wide. The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia, 1 and the dysbindin-1 gene is also associated with cognitive functions. [2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage. These isoforms are divided into three classic groups: 10 type I (previously known as acetylcholine receptor inducing activity, heregulin or neu differentiation factor), type II (glia growth factor) and type III (cysteine-rich domain containing), which are based on distinct amino termini. Additional NRG-1 5¢ exons have

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“…Lithium has been shown to increase the expression of the antiapoptotic gene BCL2 [4] and also to increase cAMP-responsive element-/binding protein-mediated gene transcription [5]. More recently, microarray techniques have been applied to study the effects of lithium on mouse brain [6,7], rat brain [8], and in human neuronal or peripheral blood cell lines [9,10,11,12,13]. These studies have reported effects of lithium on the expression of a number of genes involved in ion channel and receptor function, signal transduction (including the phosphatidylinositol system), neuroprotective mechanisms, endothelial growth factor, energy metabolism, and thyroid function.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Background: This study investigated the effect of lithium monotherapy on peripheral lymphocyte gene expression in bipolar disorder (BD). Method: Twenty-two medication-free bipolar subjects (11 hypomanic, 11 depressed) were started on lithium monotherapy. Closely matched healthy subjects (n = 15) were included as controls but did not receive treatment. Blood RNA samples were collected at baseline and after 2 and 8 weeks of treatment. RNA expression was measured using the Affymetrix GeneChip® Human Gene 1.0 ST Array followed by Ingenuity pathways analysis. The results for the contrast of weeks 2 and 8 were not significantly different and were combined. Results: In BD subjects, 56 genes showed significant (false discovery rate <0.1) expression changes from baseline; the effect sizes and directions for all of these were similar at weeks 2 and 8. Among these were immune-related genes (IL5RA, MOK, IFI6, and RFX2), purinergic receptors (P2RY14, P2RY2, and ADORA3) and signal transduction-related genes (CAMK1 and PIK3R6). Pathway and upstream regulator analysis also revealed that lithium altered several immune- and signal transduction-related functions. Differentially expressed genes did not correlate with week 8 clinical response, but other genes involved in protein synthesis and degradation did. Conclusion: Peripheral gene expression may serve as a biomarker of lithium effect.

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Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Cited by 46 publications

References 44 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

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

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