Abstract
This study explored the differences in glycogen synthase kinase-3 beta (GSK3β) gene polymorphisms between patients with schizophrenia and healthy controls and investigated the association between gene polymorphisms and plasma concentration of aripiprazole. We enrolled 127 patients with schizophrenia and 125 healthy controls from southern Fujian. The genotypes of the rs6438552, rs12630592, and rs3732361 loci of GSK3β were evaluated by sequencing with amplified polymerase chain reaction, and the plasma concentration of aripiprazole was determined by high-performance liquid chromatography-tandem mass spectrometry. All three loci of GSK3β had three genotypes each. The genotype distribution in each locus was not significantly different, but there was a significant difference in the allele frequency between the schizophrenia and control groups within each locus. Linkage disequilibrium analyses of the three single-nucleotide polymorphisms (SNPs) revealed strong linkage. The haplotype analysis results showed two haplotypes in the three SNPs of GSK3β. The plasma concentrations, dose-corrected concentrations, and normalized concentrations of aripiprazole were significantly different among the different genotypes of the three SNPs. In conclusion, the rs6438552, rs12630592, and rs3732361 loci of GSK3β may be involved in schizophrenia, and GSK3β gene polymorphism may be correlated with the plasma concentration of aripiprazole.
Similar content being viewed by others
References
Adli M, Hollinde DL, Stamm T, Wiethoff K, Tsahuridu M, Kirchheiner J, Heinz A, Bauer M (2007) Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta -50T/C single nucleotide polymorphism. Biol Psychiatry 62(11):1295–1302. https://doi.org/10.1016/j.biopsych.2007.03.023
Beaulieu JM (2012) A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. J Psychiatry Neurosci 37(1):7–16. https://doi.org/10.1503/jpn.110011
Benedetti F, Poletti S, Radaelli D, Bernasconi A, Cavallaro R, Falini A, Lorenzi C, Pirovano A, Dallaspezia S, Locatelli C, Scotti G, Smeraldi E (2010) Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-beta activity. Genes Brain Behav 9(4):365–371. https://doi.org/10.1111/j.1601-183X.2010.00566.x
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. https://doi.org/10.1176/appi.ajp.2012.12070908
Casey AB, Canal CE (2017) Classics in Chemical Neuroscience: Aripiprazole. ACS Chem Neurosci 8(6):1135–1146. https://doi.org/10.1021/acschemneuro.7b00087
Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, McGrath JJ, Whiteford HA (2018) Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull 44(6):1195–1203. https://doi.org/10.1093/schbul/sby058
Chen Y, Hua S, Wang W, Fan W, Tang W, Zhang Y, Zhang C (2020) A comprehensive analysis of GSK3B variation for schizophrenia in Han Chinese individuals. Asian J Psychiatr 47:101832. https://doi.org/10.1016/j.ajp.2019.10.012
Divac N, Prostran M, Jakovcevski I, Cerovac N (2014) Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int 2014:656370. https://doi.org/10.1155/2014/656370
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36(2):131–137. https://doi.org/10.1038/ng1296
Girdhar K, Hoffman GE, Jiang Y, Brown L, Kundakovic M, Hauberg ME, Francoeur NJ, Wang YC, Shah H, Kavanagh DH, Zharovsky E, Jacobov R, Wiseman JR, Park R, Johnson JS, Kassim BS, Sloofman L, Mattei E, Weng Z, Sieberts SK, Peters MA, Harris BT, Lipska BK, Sklar P, Roussos P, Akbarian S (2018) Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci 21(8):1126–1136. https://doi.org/10.1038/s41593-018-0187-0
Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65(4):391–426. https://doi.org/10.1016/s0301-0082(01)00011-9
Hu G, Yang C, Zhao L, Fan Y, Lv Q, Zhao J, Zhu M, Guo X, Bao C, Xu A, Jie Y, Jiang Y, Zhang C, Yu S, Wang Z, Li Z, Yi Z (2018) The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population. Prog Neuropsychopharmacol Biol Psychiatry 81:187–193. https://doi.org/10.1016/j.pnpbp.2017.10.017
Inkster B, Nichols TE, Saemann PG, Auer DP, Holsboer F, Muglia P, Matthews PM (2009) Association of GSK3beta polymorphisms with brain structural changes in major depressive disorder. Arch Gen Psychiatry 66(7):721–728. https://doi.org/10.1001/archgenpsychiatry.2009.70
Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, O’Donovan M, Correll CU, Kane JM, Van Os J, Insel TR (2015) Schizophrenia Nat Rev Dis Primers 1:15067. https://doi.org/10.1038/nrdp.2015.67
Kirschbaum KM, Muller MJ, Malevani J, Mobascher A, Burchardt C, Piel M, Hiemke C (2008) Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects. World J Biol Psychiatry 9(3):212–218. https://doi.org/10.1080/15622970701361255
Kozlovsky N, Shanon-Weickert C, Tomaskovic-Crook E, Kleinman JE, Belmaker RH, Agam G (2004) Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. J Neural Transm (vienna) 111(12):1583–1592. https://doi.org/10.1007/s00702-004-0166-3
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. https://doi.org/10.1002/ana.20691
Li YC, Panikker P, Xing B, Yang SS, Alexandropoulos C, McEachern EP, Akumuo R, Zhao E, Gulchina Y, Pletnikov MV, Urs NM, Caron MG, Elefant F, Gao WJ (2020) Deletion of glycogen synthase kinase-3beta in d2 receptor-positive neurons ameliorates cognitive impairment via NMDA receptor-dependent synaptic plasticity. Biol Psychiatry 87(8):745–755. https://doi.org/10.1016/j.biopsych.2019.10.025
Li J, Zeng F, Deng J, Zhu J, Li L, Zhang T, Liu J, Zhang LL, Gao CY, Zhang M, Xu ZQ, Zhou HD, Wang YJ (2014) The association between single nucleotide polymorphisms of GSK 3beta gene and sporadic Alzheimer’s disease in a cohort of southern Chinese Han population. Neurotox Res 26(4):447–453. https://doi.org/10.1007/s12640-014-9491-y
Li M, Mo Y, Luo XJ, Xiao X, Shi L, Peng YM, Qi XB, Liu XY, Yin LD, Diao HB, Su B (2011) Genetic association and identification of a functional SNP at GSK3beta for schizophrenia susceptibility. Schizophr Res 133(1–3):165–171. https://doi.org/10.1016/j.schres.2011.09.013
Meng J, Shi Y, Zhao X, Zhou J, Zheng Y, Tang R, Ma G, Zhu X, He Z, Wang Z, Xu Y, Feng G, He L (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. https://doi.org/10.1016/j.jpsychires.2007.01.005
Mizuki Y, Sakamoto S, Okahisa Y, Yada Y, Hashimoto N, Takaki M, Yamada N (2021) Mechanisms underlying the comorbidity of schizophrenia and type 2 diabetes mellitus. Int J Neuropsychopharmacol 24(5):367–382. https://doi.org/10.1093/ijnp/pyaa097
Pan B, Chen J, Lian J, Huang XF, Deng C (2015) Unique effects of acute aripiprazole treatment on the dopamine D2 receptor downstream cAMP-PKA and Akt-GSK3beta signalling pathways in rats. PLoS ONE 10(7):e0132722. https://doi.org/10.1371/journal.pone.0132722
Park PW, Seo YH, Ahn JY, Kim KA, Park JY (2009) Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients. J Clin Pharm Ther 34(5):569–574. https://doi.org/10.1111/j.1365-2710.2009.01057.x
Rampino A, Torretta S, Gelao B, Veneziani F, Iacoviello M, Marakhovskaya A, Masellis R, Andriola I, Sportelli L, Pergola G, Minelli A, Magri C, Gennarelli M, Vita A, Beaulieu JM, Bertolino A, Blasi G (2021) Evidence of an interaction between FXR1 and GSK3beta polymorphisms on levels of negative symptoms of schizophrenia and their response to antipsychotics. Eur Psychiatry 64(1):e39. https://doi.org/10.1192/j.eurpsy.2021.26
Sunada N, Takekita Y, Nonen S, Wakeno M, Koshikawa Y, Ogata H, Kinoshita T, Kato M (2019) Brain volume-related polymorphisms of the glycogen synthase kinase-3beta gene and their effect on antidepressant treatment in major depressive disorder. Neuropsychobiology 78(3):136–144. https://doi.org/10.1159/000500614
Vehof J, Burger H, Wilffert B, Al Hadithy A, Alizadeh BZ, Snieder H, investigators G, (2012) Clinical response to antipsychotic drug treatment: association study of polymorphisms in six candidate genes. Eur Neuropsychopharmacol 22(9):625–631. https://doi.org/10.1016/j.euroneuro.2012.01.006
Waade RB, Christensen H, Rudberg I, Refsum H, Hermann M (2009) Influence of comedication on serum concentrations of aripiprazole and dehydroaripiprazole. Ther Drug Monit 31(2):233–238. https://doi.org/10.1097/FTD.0b013e3181956726
Wang JR, Sun PH, Ren ZX, Meltzer HY, Zhen XC (2017) GSK-3beta interacts with dopamine D1 receptor to regulate receptor function: implication for prefrontal cortical D1 receptor dysfunction in schizophrenia. CNS Neurosci Ther 23(2):174–187. https://doi.org/10.1111/cns.12664
Yang J, Ke S, Qiao Z, Yang X, Qiu X, Song X, Zhao E, Zhou J, Zhao M, Yang Y, Fang D, Cao D (2020) Interactions between glycogen synthase kinase-3beta gene polymorphisms, negative life events, and susceptibility to major depressive disorder in a chinese population. Front Psychiatry 11:503477. https://doi.org/10.3389/fpsyt.2020.503477
Zhang Y, You X, Li S, Long Q, Zhu Y, Teng Z, Zeng Y (2020) Peripheral blood leukocyte RNA-Seq identifies a set of genes related to abnormal psychomotor behavior characteristics in patients with schizophrenia. Med Sci Monit 26:e922426. https://doi.org/10.12659/MSM.922426
Zheng P, Hu M, Xie Y, Yu Y, Jaaro-Peled H, Huang XF (2019) Aripiprazole and haloperidol protect neurite lesions via reducing excessive D2R-DISC1 complex formation. Prog Neuropsychopharmacol Biol Psychiatry 92:59–69. https://doi.org/10.1016/j.pnpbp.2018.12.007
Zhang JP, Robinson DG, Gallego JA, John M, Yu J, Addington J, Tohen M, Kane JM, Malhotra AK, Lencz T (2015) Association of a schizophrenia risk variant at the DRD2 locus with antipsychotic treatment response in first-episode psychosis. Schizophr Bull 41(6):1248–1255. https://doi.org/10.1093/schbul/sbv116
Acknowledgements
We would like to thank Editage (www.editage.cn) for English language editing.
Funding
This work was supported by the Medical Science and Technology Planning Project of Xiamen (Grant number 3502Z20194081) and National Nature Science Foundation of China (Grant number 81871058).
Author information
Authors and Affiliations
Contributions
Zhizhong Xu: Conceptualization, investigation, writing—original draft. Chunyan Wen: Formal analysis, writing—review and editing. Yinghua Huang: Methodology. Qianfa Yuan: Investigation. Xianhua Zhang: Investigation, methodology. Duoduo Lin: Resources. Liangsheng Liu: Resources. Wenqiang Wang: Conceptualization, project administration, funding acquisition.
Corresponding authors
Ethics declarations
Ethics Approval
This study was approved by the Ethics Committee of Xiamen Xianyue Hospital and complied with the ethical requirements of the declaration of Helsinki.
Consent to Participate
Informed consent was obtained from all individual participants included in the study.
Consent to Publish
Not applicable.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Xu, Z., Wen, C., Huang, Y. et al. Effects of Glycogen Synthase Kinase-3 Beta Gene Polymorphisms on the Plasma Concentration of Aripiprazole in Chinese Patients with Schizophrenia: A Preliminary Study. J Mol Neurosci 73, 76–83 (2023). https://doi.org/10.1007/s12031-022-02079-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-022-02079-7