Polymorphic variants of genes of BDNF-mediated protein kinase signaling pathways in patients with schizophrenia: association analysis and functional annotation of genes

Polymorphic variants of genes of BDNF-mediated protein kinase signaling pathways in patients with schizophrenia: association analysis and functional annotation of genes

 

Authors

 

A.S. Boiko

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

D.Z. Paderina

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

E.V. Mikhalitskaya

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

I.S. Kopnov

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation; Federal State Budgetary Educational Institution of Higher Education “Siberian State Medical University” of the Ministry of Health of the Russian Federation, Tomsk, Russian Federation

E.G. Kornetova

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation

S.A. Ivanova

Mental Health Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation; Federal State Budgetary Educational Institution of Higher Education “Siberian State Medical University” of the Ministry of Health of the Russian Federation, Tomsk, Russian Federation

 

https://doi.org/10.26617/1810-3111-2026-1(130)-5-17

 

Journal: Siberian Herald of Psychiatry and Addiction Psychiatry. 2026; 1 (130):  5-17.

 

Abstract

Background. Many studies examine schizophrenia from the perspective of neurotransmitter system dysfunction and within the framework of the neuroimmune inflammation hypothesis. However, insufficient attention has been paid to the mechanisms of neuroplasticity and signal transduction, which undoubtedly contribute to the pathological process. Polymorphic variants of genes encoding BDNF-mediated protein kinase signaling pathways in patients with schizophrenia may play a role in the development of schizophrenia. Objective: to conduct an association analysis of polymorphic variants of the brain-derived neurotrophic factor gene and genes encoding main proteins involved in the regulation of intracellular signaling pathways (AKT1, MAPK, GSK3β, CREB1genes) in patients with schizophrenia and to functionally annotate the genes studied. Material and Methods. Genotyping of DNA samples from 433 patients with schizophrenia and 193 healthy individuals of the Russian descent of the Siberian region was carried out for polymorphic variants of the studied genes BDNF(rs6265, rs11030104), GSK3β(rs13321783, rs6805251, rs334558), AKT1(rs1130233, rs3730358), MAPK(rs8136867, rs3810608), CREB1 (rs6740584) using real-time PCR. To create a network of protein-protein interactions of the studied genes, the STRING online service (https://string-db.org/) was used; functional annotation of genes was carried out using the functionality of the Gene Ontology database (https://geneontology.org/). Results. Significant associations were identified for polymorphic variants of the GSK3βand AKT1 genes. Patients with schizophrenia exhibited a higher frequency of the AG genotype and a reduced frequency of the GG genotype of the rs334558 polymorphism (GSK3βgene). Associations with schizophrenia were identified for two polymorphic variants of the AKT1 gene (rs3730358 and rs1130233): a decrease in the frequency of the GG genotype and an increase in the frequency of the AG genotype of the polymorphism rs3730358; the T allele of the polymorphism rs1130233 had a risk effect to schizophrenia, the C allele reduced the risk of developing the disease. Our results confirmed that alterations in the AKT1-GSK3βsignaling pathway play an important role in the pathogenesis of schizophrenia, and we can consider AKT1 and GSK3βas potential schizophrenia susceptibility genes.

 

Keywords: schizophrenia, polymorphic variant, BDNF, protein kinase signaling pathways, GSK3β, AKT1, MAPK, CREB1, functional gene annotation.

 

Article (pdf)

 

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Materials  

For citation: Boiko A.S., Paderina D.Z., Mikhalitskaya E.V., Kopnov I.S., Kornetova E.G., Ivanova S.A. Polymorphic variants of genes of BDNF-mediated protein kinase signaling pathways in patients with schizophrenia: association analysis and functional annotation of genes. Siberian Herald of Psychiatry and Addiction Psychiatry.2026; 1 (130): 5-17. https://doi.org/10.26617/1810-3111-2026-1(130)-5-17

 

REFERENCES

  1. Shmukler AB. Schizophrenia. Moscow: GEOTAR-Media, 2017:176 (in Russian).
  2. Semke AV, Vetlugina TP, Ivanova SA, Rakhmazova LD, Kornetova EG, Fedorenko OYu, Lobacheva O.A. Biological and clinical-social mechanisms of development of endogenous mental diseases. Siberian Herald of Psychiatry and Addiction Psychiatry. 2011;4(67):19-23 (in Russian).
  3. Kornetova EG, Semke AV, Kornetov AN, Ivanova SA, Lobacheva OA, Semenyuk KA, Boiko AS, Bokhan NA. Schizophrenia: biopsychosocial model and constitutional-biological approach. Tomsk: Integrated Casework Ltd, 2018. 174 (in Russian).
  4. Nagi Y, Al-Ajlouni YA, Al Ta'ani O, Bak M, Makarem N, Haidar A. The burden of mental disorders and substance abuse in the Middle East and North Africa (MENA) region: findings from the Global Burden of Disease Study. Soc Psychiatry Psychiatr Epidemiol. 2026 Jan;61(1):151-168. https://doi.org/10.1007/s00127-025-02885-5. Epub 2025 Apr 8. PMID: 40198332.
  5. Boiko AS, Bokhan NA, Buneva VN, Vetlugina TP, Zozulya SA, Ivanova SA, Klyushnik TP, Kornetova EG, Losenkov IS, Oleychik IV, Semke AV, Smirnova LP, Uzbekov MG, Fedorenko OYu. Biological markers of schizophrenia: search and clinical application. Novosibirsk: Siberian Branch of the Russian Academy of Sciences, 2017:148 (in Russian).
  6. Hakami MA. Molecular signatures and emerging therapeutic targets in schizophrenia: a biomarker-centric perspective in psychiatric disorders. Schizophr Res. 2025;282:1-18. https://doi.org/10.1016/j.schres.2025.05.026.
  7. Kuepper R, Skinbjerg M, Abi-Dargham A. The dopamine dysfunction in schizophrenia revisited: new insights into topography and course. Handb Exp Pharmacol. 2012;(212):1-26. https://doi.org/10.1007/978-3-642-25761-2_1. PMID: 23129326.
  8. Ermakov E, Mednova I, Boiko A, Ivanova S. Neuroinflammation in schizophrenia: An overview of evidence and implications for pathophysiology. J Integr Neurosci. 2025 Jul 25;24(7):27636.https://doi.org/10.31083/JIN27636. PMID: 40767005.
  9. Fominova UN, Gurina OI, Shepeleva II, Popova TN, Kekelidze ZI, Chekhonin VP. Brain-derived neurotrophic factor: structure and interaction with receptors. Russian Journal of Psychiatry. 2018;4:64-72 (in Russian).
  10. Gulyaeva NV. Molecular mechanisms of neuroplasticity: An expanding universe. Biochemistry (Moscow). 201782(3):237-242.https://doi.org/10.1134/S0006297917030014. PMID: 28320264.
  11. Kesidou E, Mitsoudis N, Damianidou O, Taloumtzis C, Tsakiridou M, Polyzoidou E, Grigoriadou E, Bakirtzis C, Spandou E, Simeonidou C. Neuroplasticity across the autism-schizophrenia continuum. Biomedicines. 2025 Nov 2;13(11):2695.https://doi.org/10.3390/biomedicines13112695. PMID: 41301788; PMCID: PMC12650127.
  12. So MT, Ullah A, Waris A, Alhumaydhi FA. The etiological role of impaired neurogenesis in schizophrenia: Interactions with inflammatory, microbiome and hormonal signaling. Int J Mol Sci. 2025 Oct 9;26(19):9814. https://doi.org/10.3390/ijms26199814. PMID: 41097077; PMCID: PMC12524466.
  13. MikhalitskayaEV, LevchukLA. Brain neuroplasticity: brain-derived neurotrophic factor and protein kinase signaling pathways (literature review). Siberian Herald of Psychiatry and Addiction Psychiatry. 2022;3(116): 44-53. https://doi.org/10.26617/1810-3111-2022-3(116)-44-53 (in Russian).
  14. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64(2):238-258. https://doi.org/10.1124/pr.111.005108. Epub 2012 Mar 8. PMID: 22407616; PMCID: PMC3310485.
  15. Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential. Transl Neurodegener. 2022;11(1):4. https://doi.org/10.1186/s40035-022-00279-0. PMID: 35090576; PMCID: PMC8796548.
  16. Levchuk LA, Vyalova NM, Mikhalitskaya EV, Semkina AA, Ivanova SA. The role of BDNF in the pathogenesis of neurological and mental disorders. Modern Problems of Science And Education. 2018;6:58 (in Russian).
  17. Nieto R, Kukuljan M, Silva H. BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Front Psychiatry. 2013;4:45. https://doi.org/10.3389/fpsyt.2013.00045. PMID: 23785335; PMCID: PMC3683823.
  18. Mohammadi A, Amooeian VG, Rashidi E. Dysfunction in brain-derived neurotrophic factor signaling pathway and susceptibility to schizophrenia, Parkinson's and Alzheimer's diseases. Curr Gene Ther. 2018;18(1):45-63. https://doi.org/10.2174/1566523218666180302163029. PMID: 29512462.
  19. Levchuk LA, Meeder EMG, Roschina OV, Loonen AJM, Boiko AS, Michalitskaya EV, Epimakhova EV, Losenkov IS, Simutkin GG, Bokhan NA, Schellekens AFA, Ivanova SA. Exploring brain derived neurotrophic factor and cell adhesion molecules as biomarkers for the transdiagnostic symptom anhedonia in alcohol use disorder and comorbid depression. Front Psychiatry. 2020 Apr 20;11:296. https://doi.org/10.3389/fpsyt.2020.00296. PMID: 32372985; PMCID: PMC7184244.
  20. Duda P, Hajka D, Wójcicka O, Rakus D, Gizak A. GSK3β: A master player in depressive disorder pathogenesis and treatment responsiveness. Cells. 2020 Mar 16;9(3):727. https://doi.org/10.3390/cells9030727. PMID: 32188010; PMCID: PMC7140610.
  21. Ivanova SA, Losenkov IS, Bokhan NA. The role of glycogen synthase kinase-3βin the pathogenesis of mental disorders. S.S. Korsakov Journal of Neurology and Psychiatry. 2014; 114(6):93-100 (in Russian).
  22. Foltran RB, Diaz SL. BDNF isoforms: a round trip ticket between neurogenesis and serotonin? J Neurochem. 2016;138(2):204-221.https://doi.org/10.1111/jnc.13658. PMID: 27167299.
  23. Barfield ET, Gourley SL. Corrigendum to "Prefrontal cortical trkB, glucocorticoids, and their interactions in stress and developmental contexts" [Neurosci. Biobehav. Rev. 95 (2018) 535-558]. Neurosci Biobehav Rev. 2019 Apr; 99:329. https://doi.org/10.1016/j.neubiorev.2019.02.007. Erratum for: Neurosci Biobehav Rev. 2018 Dec;95:535-558. https://doi.org/10.1016/j.neubiorev.2018.10.015. PMID: 30803819.
  24. Leal G, Comprido D, Duarte CB. BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology. 2014;76(PtC):639-656. https://doi.org/10.1016/j.neuropharm.2013.04.005. Epub 2013 Apr 16. PMID: 23602987.
  25. Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011 Oct;23(10):1515-27. https://doi.org/10.1016/j.cellsig.2011.05.004. PMID: 21620960.
  26. Koga Y, Tsurumaki H, Aoki-Saito H, Sato M, Yatomi M, Takehara K, Hisada T. Roles of cyclic amp response element binding activation in the ERK1/2 and p38 MAPK signalling pathway in central nervous system, cardiovascular system, osteoclast differentiation and mucin and cytokine production. Int J Mol Sci. 2019 Mar 17;20(6):1346.https://doi.org/10.3390/ijms20061346. PMID: 30884895; PMCID: PMC6470985.
  27. Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res. 2015;35(6):600-604. https://doi.org/10.3109/10799893.2015.1030412. Epub 2015 Jun 22. PMID: 26096166.
  28. Levchenko A, Losenkov IS, Vyalova NM, Simutkin GG, Bokhan NA, Wilffert B, Loonen AJ, Ivanova SA. The functional variant rs334558 of GSK3B is associated with remission in patients with depressive disorders. Pharmgenomics Pers Med. 2018;11:121-126. https://doi.org/10.2147/PGPM.S171423. PMID: 30050316; PMCID: PMC6055890.
  29. Howell KR, Law AJ. Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development. Schizophr Res. 2020;217:95-104. https://doi.org/10.1016/j.schres.2019.08.036. Epub 2019 Sep 12. PMID: 31522868; PMCID: PMC7065975.
  30. Boiko AS, Mikhalitskaya EV, Kornetova EG, Bokhan NA, Ivanova SA. Protein kinase expression of the AKT/mTOR signaling pathway in peripheral mononuclear cells of schizophrenia patients: A pilot study. NeuroSci. 2025;6(4):116.https://doi.org/10.3390/neurosci6040116.
  31. Boiko AS, Mednova IA, Mikhalitskaya EV, Paderina DZ, Petkun DA, Kornetova EG, Bokhan NA, Ivanova SA. BDNF gene polymorphisms and BDNF serum concentration in schizophrenia patients: a pilot study. Front Psychiatry. 2025 May 19;16:1556079. https://doi.org/10.3389/fpsyt.2025.1556079. PMID: 40458783; PMCID: PMC12127303.
  32. Boiko AS, Pozhidaev IV, Mikhalitskaya EV, Paderina DZ, Vyalova NM, Kornetova EG, Bokhan NA, Ivanova SA. The role of polymorphic variants of neuroplasticity genes and protein kinases in the formation of an unfavorable course of schizophrenia. Psychiatry, Psychotherapy and Clinical Psychology. 2025;16(1):13-22. https://doi.org/10.34883/PI.2025.16.1.001 (in Russian).
  33. Kornetova EG, Goncharova AA, Kornetov AN, Davydov AA, Dubrovskaya VV, Semke AV, Bokhan NA. The relationship between suicidal behavior and hopelessness with akathisia in patients with schizophrenia. Suicidology. 2018;3(32):63-70. https://doi.org/10.32878/suiciderus.18-09-03(32)-63-70(in Russian).
  34. Mosolov SN. Scales of psychometric assessment of schizophrenia symptoms and the concept of positive and negative disorders. Moscow: Novy Tsvet, 2001:238(inRussian).
  35. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet. 2004;36(2):131-137. https://doi.org/10.1038/ng1296. Epub 2004 Jan 25. PMID: 14745448.
  36. Lee KY, Joo EJ, Jeong SH, Kang UG, Roh MS, Kim SH, Song JY, Hwang JY, Kim SG, Lee N, Ahn YM, Kim YS. No association between AKT1 polymorphism and schizophrenia: a case-control study in a Korean population and a meta-analysis. Neurosci Res. 2010 Mar;66(3):238-45. https://doi.org/10.1016/j.neures.2009.11.005. Epub 2009 Nov 28. PMID: 19931325.
  37. Millischer V, Matheson GJ, Martinsson L, Römer Ek I, Schalling M, Lavebratt C, Backlund L. AKT1 and genetic vulnerability to bipolar disorder. Psychiatry Res. 2020;284:112677. https://doi.org/10.1016/j.psychres.2019.112677. Epub 2019 Nov 4. PMID: 31810747.
  38. Terrisse R, Stephan F, Walter M, Lemey C. Predicting the evolution from first-episode psychosis to mood or psychotic disorder: a systematic review of biological markers. J Affect Disord. 2025;374:26-38. https://doi.org/10.1016/j.jad.2025.01.015.
  39. Chow TJ, Tee SF, Yong HS, Tang PY. Genetic association of TCF4 and AKT1 gene variants with the age at onset of schizophrenia. Neuropsychobiology. 2016;73(4):233-240.https://doi.org/10.1159/000446285. Epub 2016 Jun 16. PMID: 27305091.
  40. Levchenko A, Vyalova N, Pozhidaev IV, Boiko AS, Osmanova DZ, Fedorenko OY, Semke AV, Bokhan NA, Wilffert B, Loonen AJM, Ivanova SA. No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia. Hum Psychopharmacol. 2019 Jan;34(1):e2685. https://doi.org/10.1002/hup.2685. Epub 2019 Jan 8. PMID: 30623492.
  41. Yang J, Ke S, Qiao Z, Yang X, Qiu X, Song X, Zhao E, Zhou J, Zhao M, Yang Y, Fang D, Cao D. Interactions between glycogen synthase kinase-3β gene polymorphisms, negative life events, and susceptibility to major depressive disorder in a Chinese population. Front Psychiatry. 2021 Feb 15;11:503477. https://doi.org/10.3389/fpsyt.2020.503477. PMID: 33658947; PMCID: PMC7917206.
  42. Liu S, Wang L, Sun N, Yang C, Liu Z, Li X, Cao X, Xu Y, Zhang K. The gender-specific association of rs334558 in GSK3β with major depressive disorder. Medicine (Baltimore). 2017 Jan;96(3):e5928. https://doi.org/10.1097/MD.0000000000005928. PMID: 28099358; PMCID: PMC5279103.
  43. Terao T, Ishii N, Hirakawa H. A specific group of patients with diagnostic conversion from depression to bipolar disorder and finally to dementia as a mental GSK-3 disease: a hypothesis. Bipolar Disord. 2020;22(4):356-359. https://doi.org/10.1111/bdi.12875. Epub 2020 Jan 5. PMID: 31742842.
  44. Levchenko A, Kanapin A, Samsonova A, Fedorenko OY, Kornetova EG, Nurgaliev T, Mazo GE, Semke AV, Kibitov AO, Bokhan NA, Gainetdinov RR, Ivanova SA. A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Mar 8;105:110134.https://doi.org/10.1016/j.pnpbp.2020.110134.Epub 2020 Oct 13. PMID: 33065217.
  45. Costemale-Lacoste JF, Colle R, Martin S, Asmar KE, Loeb E, Feve B, Verstuyft C, Trabado S, Ferreri F, Haffen E, Polosan M, Becquemont L, Corruble E. Glycogen synthase kinase-3β genetic polymorphisms and insomnia in depressed patients: A prospective study. J Affect Disord. 2018 Nov;240:230-236. https://doi.org/10.1016/j.jad.2018.07.062. Epub 2018 Jul 24. PMID: 30081294.
  46. Tang H, Shen N, Jin H, Liu D, Miao X, Zhu LQ. GSK-3β polymorphism discriminates bipolar disorder and schizophrenia: a systematic meta-analysis. Mol Neurobiol. 2013 Dec;48(3):404-11. https://doi.org/10.1007/s12035-013-8414-x. Epub 2013 Feb 27. PMID: 23440732.
  47. BoikoAS, PaderinaDZ, IvanovaSA. Regulatory potential of polymorphic variants of genes of BDNF-mediated protein kinase signaling pathways associated with schizophrenia. Siberian Herald of Psychiatry and Addiction Psychiatry. 2025; 3 (128): 5-16. https://doi.org/10.26617/1810-3111-2025-3(128)-5-16 (in Russian).
  48. Nica AC, Dermitzakis ET. Expression quantitative trait loci: present and future. Philos Trans R Soc Lond B Biol Sci. 2013 May 6;368(1620):20120362. https://doi.org/10.1098/rstb.2012.0362. PMID: 23650636; PMCID: PMC3682727.