Molecular Biology Reports

, Volume 41, Issue 9, pp 5711–5718 | Cite as

Meta-analysis demonstrates lack of association of the GSK3B −50C/T polymorphism with risk of bipolar disorder

  • Guodi Chen
  • Jun Tang
  • Guangwei Yu
  • Yiping Chen
  • Liancong Wang
  • Yao ZhangEmail author


Published data on the association between GSK3B −50C/T (rs334558) and bipolar disorder (BD) are inconclusive. We performed this meta-analysis to evaluate the relationship of this single-nucleotide polymorphism with the susceptibility, and with the age at onset of BD. A literature search was conducted though PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure databases to identify relevant studies up to February 14, 2014. We identified a total of 6 publications including 1,251 cases and 1,804 controls to investigate the effect of GSK3B −50C/T on BD risk, and found no significant association in any genetic models (C vs. T: OR = 1.03, 95 % CI: 0.92–1.15; CC vs. TT+TC: OR = 1.04, 95 % CI: 0.84–1.28; TC+CC vs. TT: OR = 1.16, 95 % CI: 0.97–1.39; and CC vs. TC vs. TT: OR = 1.08, 95 % CI: 0.96–1.22). Subgroup analysis by ethnicity did not change the results. The association between GSK3B −50C/T and age at onset of BD was explored by 6 identified studies with a total of 659 BD type I patients. Similarly, we did not observe significant results in any genetic models (TC+CC vs. TT: SMD = 0.20, 95 % CI: −0.07 to 0.47; CC vs. TT+TC: SMD = 0.11, 95 % CI: −0.10 to 0.32; CC vs. TT: SMD = 0.32, 95 % CI: −0.13 to 0.77). The power analysis and tests for publication bias ensured the reliability of our results. In summary, this meta-analysis suggests that the functional polymorphism −50C/T within the GSK3B gene promoter is unlikely to relate with BD risk. However, more larger and well-designed studies are still needed to yield a conclusive result on the topic.


GSK3B Polymorphism Age at onset Meta-analysis Bipolar disorder 


Conflict of interest

None declared.

Supplementary material

11033_2014_3441_MOESM1_ESM.doc (48 kb)
Supplementary material 1 (DOC 47 kb)
11033_2014_3441_MOESM2_ESM.tif (801 kb)
Supplementary Fig. S1 Forest plots and Begg’s funnel plots for the overall association between GSK3B −50C/T and bipolar disorder risk in other genetic models. ab Forest plot (a) and Begg’s funnel plot (b) in the CC versus TT+TC model (the recessive model). cd Forest plot (c) and Begg’s funnel plot (d) in the TC+CC versus TT model (the dominant model). ef Forest plot (e) and Begg’s funnel plot (f) in the CC versus TC versus TT model (the log-additive model). (TIFF 801 kb)
11033_2014_3441_MOESM3_ESM.tif (538 kb)
Supplementary Fig. S2 Forest plots and Begg’s funnel plots for the overall association between GSK3B −50C/T and the age at onset of disorder risk in other genetic models. ab Forest plot (a) and Begg’s funnel plot (b) in the CC versus TT+TC model (the recessive model). cd Forest plot (c) and Begg’s funnel plot (d) in the CC versus TT model. (TIFF 537 kb)
11033_2014_3441_MOESM4_ESM.tif (608 kb)
Supplementary Fig. S3 Statistical power analysis. It presents the study power for detecting a significant association between GSK3B −50C/T and bipolar disorder risk based on the allelic data in this meta-analysis (α = 0.05, controls/cases ratio = 1.44, and C allele frequency in controls = 0.441). The power in our study is 45, 76 and 94 % when OR is 1.10, 1.15 and 1.20, respectively. (TIFF 607 kb)


  1. 1.
    Smoller JW, Finn CT (2003) Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet 123C(1):48–58. doi: 10.1002/ajmg.c.20013 CrossRefPubMedGoogle Scholar
  2. 2.
    Kessler RC, Adler L, Ames M, Barkley RA, Birnbaum H, Greenberg P, Johnston JA, Spencer T, Ustun TB (2005) The prevalence and effects of adult attention deficit/hyperactivity disorder on work performance in a nationally representative sample of workers. J Occup Environ Med/Am Coll Occup Environ Med 47(6):565–572CrossRefGoogle Scholar
  3. 3.
    Ketter TA (2010) Diagnostic features, prevalence, and impact of bipolar disorder. J Clin Psychiatry 71(6):e14. doi: 10.4088/JCP.8125tx11c CrossRefPubMedGoogle Scholar
  4. 4.
    Novick DM, Swartz HA, Frank E (2010) Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord 12(1):1–9. doi: 10.1111/j.1399-5618.2009.00786.x PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Chatterton ML, Ke X, Lewis BE, Rajagopalan K, Lazarus A (2008) Impact of bipolar disorder on the family: utilization and cost of health care resources. P & T 33(1):15–34Google Scholar
  6. 6.
    Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, Jin R, Merikangas KR, Simon GE, Wang PS (2006) Prevalence and effects of mood disorders on work performance in a nationally representative sample of US workers. Am J Psychiatry 163(9):1561–1568. doi: 10.1176/appi.ajp.163.9.1561 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, Schulze TG, Cichon S, Rietschel M, Nothen MM, Georgi A, Schumacher J, Schwarz M, Abou Jamra R, Hofels S, Propping P, Satagopan J, Detera-Wadleigh SD, Hardy J, McMahon FJ (2008) A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13(2):197–207. doi: 10.1038/ PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Craddock N (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40(9):1056–1058. doi: 10.1038/ng.209 PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, de Bakker PI, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D, Scolnick EM, Daly MJ, Blackwood DH, Gurling HM, Purcell SM (2008) Whole-genome association study of bipolar disorder. Mol Psychiatry 13(6):558–569. doi: 10.1038/ PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W, Byerley W, Coryell W, Craig D, Edenberg HJ, Eskin E, Foroud T, Gershon E, Greenwood TA, Hipolito M, Koller DL, Lawson WB, Liu C, Lohoff F, McInnis MG, McMahon FJ, Mirel DB, Murray SS, Nievergelt C, Nurnberger J, Nwulia EA, Paschall J, Potash JB, Rice J, Schulze TG, Scheftner W, Panganiban C, Zaitlen N, Zandi PP, Zollner S, Schork NJ, Kelsoe JR (2009) Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 14(8):755–763. doi: 10.1038/mp.2009.43 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Djurovic S, Gustafsson O, Mattingsdal M, Athanasiu L, Bjella T, Tesli M, Agartz I, Lorentzen S, Melle I, Morken G, Andreassen OA (2010) A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample. J Affect Disord 126(1–2):312–316. doi: 10.1016/j.jad.2010.04.007 CrossRefPubMedGoogle Scholar
  12. 12.
    Sklar P et al (2011) Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 43(10):977–983. doi: 10.1038/ng.943 PubMedCentralCrossRefGoogle Scholar
  13. 13.
    Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR (1992) Glycogen synthase kinase-3: functions in oncogenesis and development. Biochim Biophys Acta 1114(2–3):147–162PubMedGoogle Scholar
  14. 14.
    Forde JE, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64(15):1930–1944. doi: 10.1007/s00018-007-7045-7 CrossRefPubMedGoogle Scholar
  15. 15.
    Prickaerts J, Moechars D, Cryns K, Lenaerts I, van Craenendonck H, Goris I, Daneels G, Bouwknecht JA, Steckler T (2006) Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J Neurosci 26(35):9022–9029. doi: 10.1523/jneurosci.5216-05.2006 CrossRefPubMedGoogle Scholar
  16. 16.
    Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS (2002) Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J Neurosci 22(24):10883–10890PubMedGoogle Scholar
  17. 17.
    Inkster B, Nichols TE, Saemann PG, Auer DP, Holsboer F, Muglia P, Matthews PM (2009) Association of GSK3 beta polymorphisms with brain structural changes in major depressive disorder. Arch Gen Psychiatry 66(7):721–728CrossRefPubMedGoogle Scholar
  18. 18.
    Kwok JB, Hallupp M, Loy CT, Chan DK, Woo J, Mellick GD, Buchanan DD, Silburn PA, Halliday GM, Schofield PR (2005) GSK3B polymorphisms alter transcription and splicing in Parkinson’s disease. Ann Neurol 58(6):829–839. doi: 10.1002/ana.20691 CrossRefPubMedGoogle Scholar
  19. 19.
    Lachman HM, Pedrosa E, Petruolo OA, Cockerham M, Papolos A, Novak T, Papolos DF, Stopkova P (2007) Increase in GSK3beta gene copy number variation in bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144B(3):259–265. doi: 10.1002/ajmg.b.30498 CrossRefPubMedGoogle Scholar
  20. 20.
    Szczepankiewicz A, Rybakowski JK, Suwalska A, Skibinska M, Leszczynska-Rodziewicz A, Dmitrzak-Weglarz M, Czerski PM, Hauser J (2006) Association study of the glycogen synthase kinase-3beta gene polymorphism with prophylactic lithium response in bipolar patients. World J Biol Psychiatry 7(3):158–161. doi: 10.1080/15622970600554711 CrossRefPubMedGoogle Scholar
  21. 21.
    Serretti A, Benedetti F, Mandelli L, Calati R, Caneva B, Lorenzi C, Fontana V, Colombo C, Smeraldi E (2008) Association between GSK-3beta −50T/C polymorphism and personality and psychotic symptoms in mood disorders. Psychiatry Res 158(2):132–140. doi: 10.1016/j.psychres.2007.06.017 CrossRefPubMedGoogle Scholar
  22. 22.
    Russ C, Lovestone S, Powell JF (2001) Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer’s disease. Mol Psychiatry 6(3):320–324. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  23. 23.
    Benedetti F, Bernasconi A, Lorenzi C, Pontiggia A, Serretti A, Colombo C, Smeraldi E (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):37–40CrossRefPubMedGoogle Scholar
  24. 24.
    Lee KY, Ahn YM, Joo EJ, Jeong SH, Chang JS, Kim SC, Kim YS (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. doi: 10.1016/j.neulet.2005.10.059 CrossRefPubMedGoogle Scholar
  25. 25.
    Nishiguchi N, Breen G, Russ C, Clair D, Collier D (2006) Association analysis of the glycogen synthase kinase-3beta gene in bipolar disorder. Neurosci Lett 394(3):243–245. doi: 10.1016/j.neulet.2005.10.042 CrossRefPubMedGoogle Scholar
  26. 26.
    Szczepankiewicz A, Skibinska M, Hauser J, Slopien A, Leszczynska-Rodziewicz A, Kapelski P, Dmitrzak-Weglarz M, Czerski PM, Rybakowski JK (2006) Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology 53(1):51–56. doi: 10.1159/000090704 CrossRefPubMedGoogle Scholar
  27. 27.
    Scassellati C, Rotondo A, Bonvicini C, Rossi G, Cassano GB, Gennarelli M (2007) Further evidence on the lack of association between glycogen synthase kinase 3beta gene polymorphisms and bipolar disorder. Psychiatr Genet 17(4):249–250. doi: 10.1097/YPG.0b013e328013d8d8 CrossRefPubMedGoogle Scholar
  28. 28.
    Lee YJ, Kim YK (2011) The impact of glycogen synthase kinase 3beta gene on psychotic mania in bipolar disorder patients. Prog Neuropsychopharmacol Biol Psychiatry 35(5):1303–1308. doi: 10.1016/j.pnpbp.2011.04.006 CrossRefPubMedGoogle Scholar
  29. 29.
    Lin YF, Huang MC, Liu HC (2013) Glycogen synthase kinase 3beta gene polymorphisms may be associated with bipolar I disorder and the therapeutic response to lithium. J Affect Disord 147(1–3):401–406. doi: 10.1016/j.jad.2012.08.025 CrossRefPubMedGoogle Scholar
  30. 30.
    Benedetti F, Serretti A, Colombo C, Lorenzi C, Tubazio V, Smeraldi E (2004) A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression. Neurosci Lett 368(2):123–126. doi: 10.1016/j.neulet.2004.06.050 CrossRefPubMedGoogle Scholar
  31. 31.
    Benedetti F, Serretti A, Pontiggia A, Bernasconi A, Lorenzi C, Colombo C, Smeraldi E (2005) Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta −50 T/C SNP. Neurosci Lett 376(1):51–55. doi: 10.1016/j.neulet.2004.11.022 CrossRefPubMedGoogle Scholar
  32. 32.
    Benedetti F, Bollettini I, Barberi I, Radaelli D, Poletti S, Locatelli C, Pirovano A, Lorenzi C, Falini A, Colombo C, Smeraldi E (2013) Lithium and GSK3-beta promoter gene variants influence white matter microstructure in bipolar disorder. Neuropsychopharmacology 38(2):313–327. doi: 10.1038/npp.2012.172 PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Yu KD, Di GH, Fan L, Chen AX, Yang C, Shao ZM (2010) Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25,703 subjects. Breast Cancer Res Treat 122(2):483–488. doi: 10.1007/s10549-009-0706-5 CrossRefPubMedGoogle Scholar
  34. 34.
    Michael JB, Jonathan JD, Dennis GA (1999) Metan-an alternative meta-analysis command. Stata Tech Bull 8(44):4–15Google Scholar
  35. 35.
    Killeen PR (2005) An alternative to null-hypothesis significance tests. Psychol Sci 16(5):345–353. doi: 10.1111/j.0956-7976.2005.01538.x PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. doi: 10.1136/bmj.327.7414.557 PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Harris RJ, Bradburn MJ, Deeks JJ, Harbord RM, Altman DG, Sterne JAC (2008) Metan: fixed- and random-effects meta-analysis. Stata J 8(1):3–28Google Scholar
  38. 38.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101CrossRefPubMedGoogle Scholar
  39. 39.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Rybakowski JK, Czerski P, Dmitrzak-Weglarz M, Kliwicki S, Leszczynska-Rodziewicz A, Permoda-Osip A, Skibinska M, Suwalska A, Szczepankiewicz A, Hauser J (2012) Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy. J Psychopharmacol (Oxford, England) 26(3):368–373. doi: 10.1177/0269881111415736 CrossRefGoogle Scholar
  41. 41.
    Benedetti F, Dallaspezia S, Lorenzi C, Pirovano A, Radaelli D, Locatelli C, Poletti S, Colombo C, Smeraldi E (2012) Gene-gene interaction of glycogen synthase kinase 3-beta and serotonin transporter on human antidepressant response to sleep deprivation. J Affect Disord 136(3):514–519. doi: 10.1016/j.jad.2011.10.039 CrossRefPubMedGoogle Scholar
  42. 42.
    Blasi G, Napolitano F, Ursini G, Di Giorgio A, Caforio G, Taurisano P, Fazio L, Gelao B, Attrotto MT, Colagiorgio L, Todarello G, Piva F, Papazacharias A, Masellis R, Mancini M, Porcelli A, Romano R, Rampino A, Quarto T, Giulietti M, Lipska BK, Kleinman JE, Popolizio T, Weinberger DR, Usiello A, Bertolino A (2013) Association of GSK-3beta genetic variation with GSK-3beta expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia. Am J Psychiatry 170(8):868–876. doi: 10.1176/appi.ajp.2012.12070908 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Guodi Chen
    • 1
  • Jun Tang
    • 2
  • Guangwei Yu
    • 1
  • Yiping Chen
    • 3
  • Liancong Wang
    • 1
  • Yao Zhang
    • 2
    Email author
  1. 1.Department of Radiation Oncology, The Second Affiliated Hospital, and Cancer InstituteZhejiang University School of MedicineHangzhouPeople’s Republic of China
  2. 2.Wuhan Mental Health Center, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  3. 3.Department of Psychiatry, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouPeople’s Republic of China

Personalised recommendations