Skip to main content
SpringerLink
Log in

Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population

  • Biological Psychiatry - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Alterations in brain-derived neurotrophic factor (BDNF)-signaling pathways may play an important role in the pathophysiology of major depressive disorder (MDD). Several lines of evidence have suggested that gene–gene interactions may confer susceptibility to MDD. The aim of this study was to analyze the single and combined effects of genes in the BDNF signal-transduction pathway on MDD in a Chinese population. We recruited 447 patients with MDD and 432 age- and gender-matched control subjects. Five SNPs in three BDNF signal-transduction pathway genes (BDNF, GSK3B and AKT1) were used in association analyses. An allelic association between the GSK3B SNP rs6782799 and MDD was found in our sample (allelic: χ2 = 5.24, P = 0.022, corrected P = 0.107; genotypic: χ2 = 5.55, P = 0.062) with an odds ratio (OR) of 1.25 (95% confidence interval (CI) 1.03–1.52). Further gene–gene interaction analyses showed a significant effect of a two-locus BDNF/GSK3B interaction with MDD (GSK3B rs6782799 and BDNF rs7124442) (corrected P = 0.011), and also for a three-locus interaction (GSK3B rs6782799, BDNF rs6265 and BDNF rs7124442) (corrected P = 0.019). Individuals carrying the combination of two risk alleles showed an OR value of 4.00 (95% CI 2.05–7.79), while those with the combination of three risk alleles gave the largest OR value of 4.46 (95% CI 2.15–9.24). Taken together, these findings support the assertion that the GSK3B gene is an important susceptibility factor for MDD in a Han Chinese population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

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 62:1295–1302

    Article  CAS  PubMed  Google Scholar 

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington

    Google Scholar 

  • Aydemir O, Deveci A, Taneli F (2005) The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 29:261–265

    Article  CAS  PubMed  Google Scholar 

  • Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, Goka E (2006) Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 30:1256–1260

    Article  CAS  PubMed  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England) 21:263–265

    Article  CAS  Google Scholar 

  • 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 368:123–126

    Article  CAS  PubMed  Google Scholar 

  • Bierut LJ, Heath AC, Bucholz KK, Dinwiddie SH, Madden PA, Statham DJ, Dunne MP, Martin NG (1999) Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women? Arch Gen Psychiatry 56:557–563

    Article  CAS  PubMed  Google Scholar 

  • Cervilla JA, Molina E, Rivera M, Torres-González F, Bellón JA, Moreno B, Luna JD, Lorente JA, Mayoral F, King M, Nazareth I, PREDICT Study Core Group, Gutiérrez B (2007) The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort. Mol Psychiatry 12:748–755

    Article  CAS  PubMed  Google Scholar 

  • Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ, Day IN, Ebrahim S, Smith GD, Shugart YY (2008) Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 147B:814–821

    Article  CAS  PubMed  Google Scholar 

  • Choi MJ, Kang RH, Lim SW, Oh KS, Lee MS (2006) Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res 1118:176–182

    Article  CAS  PubMed  Google Scholar 

  • Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121

    Article  PubMed  Google Scholar 

  • Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66:87–98

    Article  PubMed  Google Scholar 

  • Dupont WD, Plummer WD Jr (1998) Power and sample size calculations for studies involving linear regression. Control Clin Trials 19:589–601

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003) Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60:804–815

    Article  CAS  PubMed  Google Scholar 

  • Foulstone EJ, Tavaré JM, Gunn-Moore FJ (1999) Sustained phosphorylation and activation of protein kinase B correlates with brain-derived neurotrophic factor and insulin stimulated survival of cerebellar granule cells. Neurosci Lett 264:125–128

    Article  CAS  PubMed  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  CAS  PubMed  Google Scholar 

  • Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65:391–426

    Article  CAS  PubMed  Google Scholar 

  • Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48:186–189

    Article  CAS  PubMed  Google Scholar 

  • Hsiung SC, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu KP (2003) Attenuated 5HT1a receptor signaling in brains of suicide victims: Involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen activated protein kinase. J Neurochem 87:182–194

    Article  CAS  PubMed  Google Scholar 

  • Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736

    Article  CAS  PubMed  Google Scholar 

  • Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM (2006) The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging 27:1834–1837

    Article  CAS  PubMed  Google Scholar 

  • Janssen J, Hulshoff Pol HE, de Leeuw FE, Schnack HG, Lampe IK, Kok RM, Kahn RS, Heeren TJ (2007) Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early- and late-onset depression. J Neurol Neurosurg Psychiatry 78:638–640

    Article  PubMed  Google Scholar 

  • Jope RS, Bijur GN (2002) Mood stabilizers, glycogen synthase kinase-3 beta and cell survival. Mol Psychiatry 7:S35–S45

    Article  CAS  PubMed  Google Scholar 

  • Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148

    Article  CAS  PubMed  Google Scholar 

  • Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136:29–37

    Article  CAS  PubMed  Google Scholar 

  • Karege F, Perroud N, Burkhardt S, Schwald M, Ballmann E, La Harpe R, Malafosse A (2007) Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims. Biol Psychiatry 61:240–245

    Article  CAS  PubMed  Google Scholar 

  • Kato M, Serretti A (2008) Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry [Epub ahead of print]

  • Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee BH, Yoon D, Han C, Kim DJ, Choi SH (2007) Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 31:78–85

    Article  CAS  PubMed  Google Scholar 

  • Li M, Li C (2008) Assessing departure from Hardy-Weinberg equilibrium in the presence of disease association. Genet Epidemiol 32:589–599

    Article  PubMed  Google Scholar 

  • Mai L, Jope RS, Li X (2002) BDNF-mediated signal transduction is modulated by GSK3Beta and mood stabilizing agents. J Neurochem 82:75–83

    Article  CAS  PubMed  Google Scholar 

  • Neumeister A, Wood S, Bonne O, Nugent AC, Luckenbaugh DA, Young T, Bain EE, Charney DS, Drevets WC (2005) Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects. Biol Psychiatry 57:935–937

    Article  PubMed  Google Scholar 

  • Park SW, Lee JG, Kong BG, Lee SJ, Lee CH, Kim JI, Kim YH (2009) Genetic association of BDNF val66met and GSK-3beta-50T/C polymorphisms with tardive dyskinesia. Psychiatry Clin Neurosci 63:433–439

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro L, Busnello JV, Cantor RM, Whelan F, Whittaker P, Deloukas P, Wong ML, Licinio J (2007) The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans. Neuroreport 18:1291–1293

    Article  CAS  PubMed  Google Scholar 

  • 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 158:132–140

    Article  CAS  PubMed  Google Scholar 

  • Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516–1518

    Article  PubMed  Google Scholar 

  • Shimizu E, Hashimoto K, Iyo M (2004) Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 126B:122–123

    Article  PubMed  Google Scholar 

  • Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–1562

    Article  CAS  PubMed  Google Scholar 

  • Sun N, Xu Y, Wang Y, Duan H, Wang S, Ren Y, Peng J, Du Q, Shen Y, Xu Q, Zhang K (2008) The combined effect of norepinephrine transporter gene and negative life events in major depression of Chinese Han population. J Neural Transm 115:1681–1686

    Article  CAS  PubMed  Google Scholar 

  • Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598

    Article  CAS  PubMed  Google Scholar 

  • Toyota T, Yamada K, Detera-Wadleigh SD, Yoshikawa T (2003) Analysis of a cluster of polymorphisms in AKT1 gene in bipolar pedigrees: a family-based association study. Neurosci Lett 339:5–8

    Article  CAS  PubMed  Google Scholar 

  • Tozzi F, Prokopenko I, Perry JD, Kennedy JL, McCarthy AD, Holsboer F, Berrettini W, Middleton LT, Chilcoat HD, Muglia P (2008) Family history of depression is associated with younger age of onset in patients with recurrent depression. Psychol Med 38:641–649

    Article  CAS  PubMed  Google Scholar 

  • Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 123B:19–22

    Article  PubMed  Google Scholar 

  • Tsai SJ, Liou YJ, Hong CJ, Yu YW, Chen TJ (2008) Glycogen synthase kinase-3beta gene is associated with antidepressant treatment response in Chinese major depressive disorder. Pharmacogenomics J 8:384–390

    Article  CAS  PubMed  Google Scholar 

  • Verhagen M, van der Meij A, van Deurzen PA, Janzing JG, Arias-Vásquez A, Buitelaar JK, Franke B (2008) Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry [Epub ahead of print]

  • Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT (2003) Control of synaptic strength, a novel function of Akt. Neuron 38:915–928

    Article  CAS  PubMed  Google Scholar 

  • Wittchen HU, Essau CA, von Zerssen D, Krieg JC, Zaudig M (1992) Lifetime and six-month prevalence of mental disorders in the Munich Follow-Up Study. Eur Arch Psychiatry Clin Neurosci 241:247–258

    Article  CAS  PubMed  Google Scholar 

  • Zanardini R, Gazzoli A, Ventriglia M, Perez J, Bignotti S, Rossini PM, Gennarelli M, Bocchio-Chiavetto L (2006) Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. J Affect Disord 91:83–86

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from National 863 program (2006AA02A407), National 973 Program (2004CB518601), International S&T Cooperation Program of China (2006DFA31440), National Natural Science Foundation of China (30770770&30971054) and Programs for Science and Technology Development of Shanxi (2007031091-3). Project supported by the Scientific Research Foundation of the Human Resource Ministry for Returned Chinese Scholars, China (Grant No. 2007-48). We thank the patients and families for their support and participation.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Psychiatry, First Hospital of Shanxi Medical University, 85 Jiefang South Road, 030001, Taiyuan, People’s Republic of China

    Kerang Zhang, Chunxia Yang, Yong Xu, Ning Sun, Hong Yang & Jinli Liu

  2. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Science and Peking Union Medical College, Tsinghua University, No. 5 Dong Dan San Tiao, 100005, Beijing, People’s Republic of China

    Qi Xu & Yan Shen

Authors
  1. Kerang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunxia Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ning Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinli Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kerang Zhang or Qi Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, K., Yang, C., Xu, Y. et al. Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population. J Neural Transm 117, 393–401 (2010). https://doi.org/10.1007/s00702-009-0360-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-009-0360-4

Keywords

Search

Navigation