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GSK-3β Polymorphism Discriminates Bipolar Disorder and Schizophrenia: A Systematic Meta-Analysis

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Abstract

Glycogen synthase kinase 3 (GSK-3) is a well-known conserved and ubiquitous protein kinase and playing a pivotal role in neurodevelopment, neurogenesis, learning/memory, and neuronal cell death. Dysfunction of GSK-3 had been seen in multiple neurodegenerative and psychiatric diseases. Bipolar disorder and schizophrenia are two common psychiatric diseases first occur in adolescence or young adulthood. They share similar risk genes as well as clinical symptoms, which make it is difficult to be discriminated from each other. Here, by using meta-analysis we reported that glycogen synthase kinase 3β promoter inactive mutant rs334558 may contribute to the development of schizophrenia not bipolar disorder. This might be used to distinguish these two diseases.

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References

  1. Bijur GN, Jope RS (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 276(40):37436–37442

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Hoshi M, Takashima A, Noguchi K et al (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci USA 93(7):2719–2723

    Article  CAS  PubMed  Google Scholar 

  3. Perez-Costas E, Gandy JC, Melendez-Ferro M et al (2010) Light and electron microscopy study of glycogen synthase kinase-3beta in the mouse brain. PLoS One 5(1):e8911

    Article  PubMed Central  PubMed  Google Scholar 

  4. Adachi A, Kano F, Tsuboi T et al (2010) Golgi-associated GSK3beta regulates the sorting process of post-Golgi membrane trafficking. J Cell Sci 123(Pt 19):3215–3225

    Article  CAS  PubMed  Google Scholar 

  5. Bijur GN, Jope RS (2003) Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. Neuroreport 14(18):2415–2419

    Article  CAS  PubMed  Google Scholar 

  6. Mukai F, Ishiguro K, Sano Y et al (2002) Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J Neurochem 81(5):1073–1083

    Article  CAS  PubMed  Google Scholar 

  7. Wexler EM, Geschwind DH (2011) DISC1: a schizophrenia gene with multiple personalities. Neuron 72(4):501–503

    Article  CAS  PubMed  Google Scholar 

  8. Jope RS (1999) Anti-bipolar therapy: mechanism of action of lithium. Mol Psychiatry 4(2):117–128

    Article  CAS  PubMed  Google Scholar 

  9. Phiel CJ, Klein PS (2001) Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 41:789–813

    Article  CAS  PubMed  Google Scholar 

  10. Detera-Wadleigh SD (2001) Lithium-related genetics of bipolar disorder. Ann Med 33(4):272–285

    Article  CAS  PubMed  Google Scholar 

  11. Gould TD, Manji HK (2002) The Wnt signaling pathway in bipolar disorder. Neuroscientist 8(5):497–511

    Article  CAS  PubMed  Google Scholar 

  12. Manji HK, Moore GJ, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46(7):929–940

    Article  CAS  PubMed  Google Scholar 

  13. Valvezan AJ, Klein PS (2012) GSK-3 and Wnt signaling in neurogenesis and bipolar disorder. Front Mol Neurosci 5:1

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Kozlovsky N, Belmaker RH, Agam G (2002) GSK-3 and the neurodevelopmental hypothesis of schizophrenia. Eur Neuropsychopharmacol 12(1):13–25

    Article  CAS  PubMed  Google Scholar 

  15. Kozlovsky N, Nadri C, Agam G (2005) Low GSK-3beta in schizophrenia as a consequence of neurodevelopmental insult. Eur Neuropsychopharmacol 15(1):1–11

    Article  CAS  PubMed  Google Scholar 

  16. Lovestone S, Killick R, Di Forti M et al (2007) Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci 30(4):142–149

    Article  CAS  PubMed  Google Scholar 

  17. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660–669

    Article  CAS  PubMed  Google Scholar 

  18. Kozlovsky N, Belmaker RH, Agam G (2000) Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 157(5):831–833

    Article  CAS  PubMed  Google Scholar 

  19. Benedetti F, Bernasconi A, Lorenzi C et al (2004) A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder. Neurosci Lett 355(1–2):37–40

    Article  CAS  PubMed  Google Scholar 

  20. Lin YF, Huang MC, Liu HC (2012) Glycogen synthase kinase 3β gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium. J Affect Disord. doi:10.1016/j.jad.2012.08.025

  21. Benedetti F, Poletti S, Radaelli D et al (2010) Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-beta activity. Gene Brain Behav 9(4):365–371

    CAS  Google Scholar 

  22. Scassellati C, Rotondo A, Bonvicini C et al (2007) Further evidence on the lack of association between glycogen synthase kinase 3beta gene polymorphisms and bipolar disorder. Psychiatr Genet 17(4):249–250

    Article  PubMed  Google Scholar 

  23. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  24. Harris RJ, Bradburn MJ, Deeks JJ et al (2008) Metan: fixed- and random-effects meta-analysis. Stata J 8(1):3–28

    Google Scholar 

  25. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  CAS  PubMed  Google Scholar 

  26. Egger M, Davey SG, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  Google Scholar 

  27. Nishiguchi N, Breen G, Russ C et al (2006) Association analysis of the glycogen synthase kinase-3beta gene in bipolar disorder. Neurosci Lett 394(3):243–245

    Article  CAS  PubMed  Google Scholar 

  28. Szczepankiewicz A, Skibinska M, Slopien A et al (2005) Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology 53(1):51–6

    Google Scholar 

  29. Ikeda M, Iwata N, Suzuki T et al (2005) No association of GSK3beta gene (GSK3B) with Japanese schizophrenia. Am J Med Genet B Neuropsychiatr Genet 134B(1):90–92

    Article  PubMed  Google Scholar 

  30. Kim T, Song J, Shin Y et al (2004) Association of a polymorphism of glycogen synthase kinase-3 beta (GSK-3 beta) gene and schizophrenia in Korean population. Int J Neuropsychopharmacol 7:S430–S430

    Google Scholar 

  31. Kim YH, Lee JG, Lee SJ (2006) Association study of the glycogen synthase kinase-3 beta (GSK-3 beta)-50T/C polymorphism with schizophrenia; association with depression and cognitive impairment. Eur Neuropsychopharmacol 16:S447–S447

    Google Scholar 

  32. Meng J, Shi Y, Zhao X et al (2008) No significant association between the genetic polymorphisms in the GSK-3 beta gene and schizophrenia in the Chinese population. J Psychiatr Res 42(5):365–370

    Article  PubMed  Google Scholar 

  33. Skibinska M, Kapelski P, Hauser J (2011) Family-based association study of glycogen synthase kinase 3 (GSK3)-beta gene polymorphism in schizophrenia. Eur Neuropsychopharmacol 21:S143–S144

    Google Scholar 

  34. Lee KY, Ahn YM, Joo EJ et al (2006) No association of two common SNPs at position −1727 A/T, -50 C/T of GSK-3 beta polymorphisms with schizophrenia and bipolar disorder of Korean population. Neurosci Lett 395(2):175–178

    Article  CAS  PubMed  Google Scholar 

  35. Szczepankiewicz A, Skibinska M, Hauser J et al (2006) Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology 53(1):51–56

    Article  CAS  PubMed  Google Scholar 

  36. Li M, Mo Y, Luo XJ et al (2011) Genetic association and identification of a functional SNP at GSK3beta for schizophrenia susceptibility. Schizophr Res 133(1–3):165–171

    Article  PubMed  Google Scholar 

  37. Souza RP, Romano-Silva MA, Lieberman JA et al (2008) Association study of GSK3 gene polymorphisms with schizophrenia and clozapine response. Psychopharmacology (Berl) 200(2):177–186

    Article  CAS  Google Scholar 

  38. Souza RP, Remington G, Chowdhury NI et al (2010) Association study of the GSK-3B gene with tardive dyskinesia in European Caucasians. Eur Neuropsychopharmacol 20(10):688–694

    Article  CAS  PubMed  Google Scholar 

  39. Hosgood HR, Menashe I, Shen M et al (2008) Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway. Carcinogenesis 29(10):1938–1943

    Article  CAS  PubMed  Google Scholar 

  40. Goodarzi MO, Antoine HJ, Pall M et al (2007) Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of polycystic ovary syndrome. Fertil Steril 87(6):1473–1476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Brunet-Gouet E, Decety J (2006) Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res 148(2–3):75–92

    Article  PubMed  Google Scholar 

  42. Picchioni MM, Murray RM (2007) Schizophrenia. BMJ 335(7610):91–95

    Article  PubMed  Google Scholar 

  43. Mcglashan TH, Fenton WS (1991) Classical subtypes for schizophrenia: literature review for DSM-IV. Schizophr Bull 17(4):609–632

    Article  CAS  PubMed  Google Scholar 

  44. van Os J, Kapur S (2009) Schizophrenia. Lancet 374(9690):635–645

    Article  PubMed  Google Scholar 

  45. Lymer GK, Job DE, William T et al (2006) Brain–behaviour relationships in people at high genetic risk of schizophrenia. NeuroImage 33(1):275–285

    Article  PubMed  Google Scholar 

  46. Kircher TT, Thienel R (2005) Functional brain imaging of symptoms and cognition in schizophrenia. Prog Brain Res 150:299–308

    Article  PubMed  Google Scholar 

  47. Ross CA, Margolis RL, Reading SA et al (2006) Neurobiology of schizophrenia. Neuron 52(1):139–153

    Article  CAS  PubMed  Google Scholar 

  48. Rapoport JL, Addington AM, Frangou S et al (2005) The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 10(5):434–449

    Article  CAS  PubMed  Google Scholar 

  49. Mao Y, Ge X, Frank CL et al (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136(6):1017–1031

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Kieseppa T, Partonen T, Haukka J et al (2004) High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 161(10):1814–1821

    Article  PubMed  Google Scholar 

  51. Badenhop RF, Moses MJ, Scimone A et al (2002) A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. Mol Psychiatry 7(6):594–603

    Article  CAS  PubMed  Google Scholar 

  52. Bailer U, Leisch F, Meszaros K et al (2002) Genome scan for susceptibility loci for schizophrenia and bipolar disorder. Biol Psychiatry 52(1):40–52

    CAS  PubMed  Google Scholar 

  53. Benedetti F, Bollettini I, Barberi I et al (2013) Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology 38(2):313–327

    Article  CAS  PubMed  Google Scholar 

  54. Inkster B, Nichols TE, Saemann PG et al (2009) Association of GSK3beta polymorphisms with brain structural changes in major depressive disorder. Arch Gen Psychiatry 66(7):721–728

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in parts by the National Natural Science Foundation of China (31201011), the New Century Excellent Talent of Education Ministry (NCET-10-0421), the Ministry of Science and Technology of China (2011DFG33250).

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Correspondence to Dan Liu, Xiaoping Miao or Ling-Qiang Zhu.

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Hui Tang, Na Shen, and Huijuan Jin contributed equally to this paper.

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Tang, H., Shen, N., Jin, H. et al. GSK-3β Polymorphism Discriminates Bipolar Disorder and Schizophrenia: A Systematic Meta-Analysis. Mol Neurobiol 48, 404–411 (2013). https://doi.org/10.1007/s12035-013-8414-x

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  • DOI: https://doi.org/10.1007/s12035-013-8414-x

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