Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity

Abstract

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (ORMET, 95% CI; 1.27 (1.10–1.47); ORMET/MET, 95% CI; 1.67 (1.19–2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ebmeier KP, Donaghey C, Steele JD . Recent developments and current controversies in depression. Lancet 2006; 367: 153–167.

    Article  PubMed  Google Scholar 

  2. Shih RA, Belmonte PL, Zandi PP . A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 2004; 16: 260–283.

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Levinson DF . The genetics of depression: a review. Biol Psychiatry 2006; 60: 84–92.

    CAS  PubMed  Google Scholar 

  5. Lopez-Leon S, Janssens AC, Gonzalez-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA et al. Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry 2008; 13: 772–785.

    Article  CAS  PubMed  Google Scholar 

  6. Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM et al. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 1990; 247: 1446–1451.

    Article  CAS  PubMed  Google Scholar 

  7. Martinowich K, Manji H, Lu B . New insights into BDNF function in depression and anxiety. Nat Neurosci 2007; 10: 1089–1093.

    Article  CAS  PubMed  Google Scholar 

  8. Willis-Owen SA, Fullerton J, Surtees PG, Wainwright NW, Miller S, Flint J . The Val66Met coding variant of the brain-derived neurotrophic factor (BDNF) gene does not contribute toward variation in the personality trait neuroticism. Biol Psychiatry 2005; 58: 738–742.

    Article  CAS  PubMed  Google Scholar 

  9. Bath KG, Lee FS . Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 2006; 6: 79–85.

    Article  PubMed  Google Scholar 

  10. Duman RS . Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 2004; 5: 11–25.

    Article  CAS  PubMed  Google Scholar 

  11. Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005; 58: 307–314.

    Article  CAS  PubMed  Google Scholar 

  12. Angelucci F, Brene S, Mathe AA . BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 2005; 10: 345–352.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005; 180: 95–99.

    Article  CAS  Google Scholar 

  15. Duman RS, Monteggia LM . A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116–1127.

    Article  CAS  PubMed  Google Scholar 

  16. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003; 54: 70–75.

    Article  CAS  PubMed  Google Scholar 

  17. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22: 231–238.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Itoh K, Hashimoto K, Kumakiri C, Shimizu E, Iyo M . Association between brain-derived neurotrophic factor 196 G/A polymorphism and personality traits in healthy subjects. Am J Med Genet B Neuropsychiatr Genet 2004; 124: 61–63.

    Article  Google Scholar 

  21. Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ . 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 2003; 123: 19–22.

    Article  Google Scholar 

  22. Gratacos M, Gonzalez JR, Mercader JM, de CR, Urretavizcaya M, Estivill X . Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case–control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 2007; 61: 911–922.

    Article  CAS  PubMed  Google Scholar 

  23. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  PubMed  Google Scholar 

  24. Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003; 23: 6690–6694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Veiel HO . A preliminary profile of neuropsychological deficits associated with major depression. J Clin Exp Neuropsychol 1997; 19: 587–603.

    Article  CAS  PubMed  Google Scholar 

  26. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 2004; 24: 4401–4411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen ZY, Ieraci A, Teng H, Dall H, Meng CX, Herrera DG et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci 2005; 25: 6156–6166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 2003; 28: 397–401.

    Article  CAS  PubMed  Google Scholar 

  29. Hettema JM, Neale MC, Myers JM, Prescott CA, Kendler KS . A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry 2006; 163: 857–864.

    Article  PubMed  Google Scholar 

  30. Kendler KS, Kuhn J, Prescott CA . The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am J Psychiatry 2004; 161: 631–636.

    Article  PubMed  Google Scholar 

  31. Strauss J, Barr CL, George CJ, Devlin B, Vetro A, Kiss E et al. Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample. Mol Psychiatry 2005; 10: 861–867.

    Article  CAS  PubMed  Google Scholar 

  32. Cohen S, Rosa A, Corsico A, Sterne A, Owen M, Korszun A et al. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and recurrent unipolar depression. Am J Med Genet B Neuropsychiatr Genet 2004; 130: 37–38.

    Google Scholar 

  33. Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van BC et al. No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies. Eur Neuropsychopharmacol 2005; 15: 491–495.

    Article  CAS  PubMed  Google Scholar 

  34. Surtees PG, Wainwright NW, Willis-Owen SA, Sandhu MS, Luben R, Day NE et al. No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. J Psychiatr Res 2007; 41: 404–409.

    Article  PubMed  Google Scholar 

  35. Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B et al. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet 2004; 131: 16–19.

    Article  Google Scholar 

  36. Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS et al. Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 387–393.

    Article  CAS  Google Scholar 

  37. Anttila S, Huuhka K, Huuhka M, Rontu R, Hurme M, Leinonen E et al. Interaction between 5-HT1A and BDNF genotypes increases the risk of treatment-resistant depression. J Neural Transm 2007; 114: 1065–1068.

    Article  CAS  PubMed  Google Scholar 

  38. Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P et al. Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 2007; 64: 410–416.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Taylor WD, Zuchner S, McQuoid DR, Steffens DC, Speer MC, Krishnan KR . Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression. Am J Geriatr Psychiatry 2007; 15: 850–857.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Iga JI, Ueno SI, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S et al. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 1003–1006.

    Article  Google Scholar 

  44. Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T et al. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry 2004; 56: 376–378.

    Article  CAS  PubMed  Google Scholar 

  45. Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH . Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 51–53.

    Article  CAS  Google Scholar 

  46. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005; 10: 208–212.

    Article  CAS  PubMed  Google Scholar 

  47. Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van BC et al. Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 34–35.

    Article  Google Scholar 

  48. Nolen-Hoeksema S . Gender differences in depression. In: Gotlib IH, Hammen CL (eds). Handbook of Depression. Guilford Press: New York, 2002, pp 492–509.

    Google Scholar 

  49. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095–3105.

    Article  PubMed  Google Scholar 

  50. Bijl RV, Ravelli A, van Zessen G . Prevalence of psychiatric disorder in the general population: results of The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Soc Psychiatry Psychiatr Epidemiol 1998; 33: 587–595.

    Article  CAS  PubMed  Google Scholar 

  51. Bijl RV, van Zessen G, Ravelli A . Psychiatric morbidity among adults in The Netherlands: the NEMESIS-Study. II. Prevalence of psychiatric disorders. Netherlands Mental Health Survey and Incidence Study. Ned Tijdschr Geneeskd 1997; 141: 2453–2460.

    CAS  PubMed  Google Scholar 

  52. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB . Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. J Affect Disord 1993; 29: 85–96.

    Article  CAS  PubMed  Google Scholar 

  53. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996; 276: 293–299.

    Article  CAS  PubMed  Google Scholar 

  54. Bierut LJ, Heath AC, Bucholz KK, Dinwiddie SH, Madden PA, Statham DJ et al. Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women? Arch Gen Psychiatry 1999; 56: 557–563.

    Article  CAS  PubMed  Google Scholar 

  55. Kendler KS, Gardner CO, Neale MC, Prescott CA . Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med 2001; 31: 605–616.

    Article  CAS  PubMed  Google Scholar 

  56. Kendler KS, Gatz M, Gardner CO, Pedersen NL . A Swedish national twin study of lifetime major depression. Am J Psychiatry 2006; 163: 109–114.

    Article  PubMed  Google Scholar 

  57. Kendler KS, Prescott CA . A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry 1999; 56: 39–44.

    Article  CAS  PubMed  Google Scholar 

  58. McGuffin P, Katz R, Watkins S, Rutherford J . A hospital-based twin register of the heritability of DSM-IV unipolar depression. Arch Gen Psychiatry 1996; 53: 129–136.

    Article  CAS  PubMed  Google Scholar 

  59. Fullerton J, Cubin M, Tiwari H, Wang C, Bomhra A, Davidson S et al. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 2003; 72: 879–890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zubenko GS, Hughes III HB, Maher BS, Stiffler JS, Zubenko WN, Marazita ML . Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet 2002; 114: 980–987.

    Article  PubMed  Google Scholar 

  61. Zubenko GS, Maher B, Hughes III HB, Zubenko WN, Stiffler JS, Kaplan BB et al. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am J Med Genet 2003; 123B: 1–18.

    Article  PubMed  Google Scholar 

  62. Hwu HG, Chang IH, Yeh EK, Chang CJ, Yeh LL . Major depressive disorder in Taiwan defined by the Chinese diagnostic Interview Schedule. J Nerv Ment Dis 1996; 184: 497–502.

    Article  CAS  PubMed  Google Scholar 

  63. Parker G, Chan B, Hadzi-Pavlovic D . Lower rates of depression in westernised Chinese in the US. J Affect Disord 2007; 104: 175–178.

    Article  PubMed  Google Scholar 

  64. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.

    Article  CAS  PubMed  Google Scholar 

  65. Munafo MR, Flint J . Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444.

    Article  CAS  PubMed  Google Scholar 

  66. Trikalinos TA, Salanti G, Zintzaras E, Ioannidis JP . Meta-analysis methods. Adv Genet 2008; 60: 311–334.

    Article  PubMed  Google Scholar 

  67. Demiryurek S, Savas HA, Igci M, Herken H, Gorucu S, Kara AF et al. Association between the 196G>A (VAL66MET) and -1360C>T (C-270T) polymorphisms of the brain-derived neurotrophic factor gene and bipolar disorder. Neurol, Psychiatry Brain Res 2006; 13: 125–130.

    Google Scholar 

  68. Tsai SJ, Hong CJ, Liu HC, Liu TY, Hsu LE, Lin CH . Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer's disease and age of onset. Neuropsychobiology 2004; 49: 10–12.

    Article  CAS  PubMed  Google Scholar 

  69. Deeks J, Higgins J, Altman D . Analysing and presenting results. In: Higgins J, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Section 8. Wiley Ltd: Chichester, UK, 2006.

    Google Scholar 

  70. Sterne JAC, Bradburn MJ, Egger M . Meta-analysis in Stata. In: Egger M, Davey SG, Altman DG (eds). Systematic Reviews in Health Care. Meta-Analysis in Context. BMJ Books: London, 2001, pp 347–369.

    Chapter  Google Scholar 

  71. Weir B . Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sinauer Associates: Sunderland, 1996.

    Google Scholar 

  72. Review Manager (RevMan) [Computer program]. Version 4.2 for Windows. The Nordic Cochrane Centre, The Cochrane Collaboration: Copenhagen, 2003.

  73. RevMan Analyses [Computer program]. Version 1.0 for Windows. In: Review Manager (RevMan) 4.2. The Nordic Cochrane Centre, The Cochrane Collaboration: Copenhagen, 2003.

  74. Lau J, Ioannidis JP, Schmid CH . Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127: 820–826.

    Article  CAS  PubMed  Google Scholar 

  75. Fleiss J . Statistical Methods for Rates and Proportions, 2nd edn, Wiley: New York, 1981.

    Google Scholar 

  76. Zintzaras E, Hadjigeorgiou GM . Association of paraoxonase 1 gene polymorphisms with risk of Parkinson's disease: a meta-analysis. J Hum Genet 2004; 49: 474–481.

    Article  PubMed  Google Scholar 

  77. Mantel N, Haenszel W . Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–748.

    CAS  PubMed  Google Scholar 

  78. Laird NM, Mosteller F . Some statistical methods for combining experimental results. Int J Technol Assess Health Care 1990; 6: 5–30.

    Article  CAS  PubMed  Google Scholar 

  79. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    Article  CAS  PubMed  Google Scholar 

  80. Whitehead A . Dealing with heterogeneity. Meta-Analysis of Controlled Clinical Trials. Wiley: Chicester, 2002, pp 151–174.

    Chapter  Google Scholar 

  81. R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2008.

  82. StataCorp [Computer program]. Stata Statistical Software: Release 8. StataCorp LP: College Station, TX, 2003.

  83. Egger M, Davey SG, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Begg CB, Mazumdar M . Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101.

    Article  CAS  PubMed  Google Scholar 

  85. Hunnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP . Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 2007; 32: 2552–2560.

    Article  PubMed  CAS  Google Scholar 

  86. Jiang X, Xu K, Hoberman J, Tian F, Marko AJ, Waheed JF et al. BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects. Neuropsychopharmacology 2005; 30: 1353–1361.

    Article  CAS  PubMed  Google Scholar 

  87. Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH et al. BDNF genotype potentially modifying the association between incident stroke and depression. Neurobiol Aging 2008; 29: 789–792.

    Article  CAS  PubMed  Google Scholar 

  88. Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007; 50: 431–438.

    Article  CAS  PubMed  Google Scholar 

  89. Kremeyer B, Herzberg I, Garcia J, Kerr E, Duque C, Parra V et al. Transmission distortion of BDNF variants to bipolar disorder type I patients from a South American population isolate. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 435–439.

    Article  CAS  Google Scholar 

  90. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL . The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002; 71: 651–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oroszi G, Lapteva L, Davis E, Yarboro CH, Weickert T, Roebuck-Spencer T et al. The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis 2006; 65: 1330–1335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rybakowski JK, Suwalska A, Skibinska M, Szczepankiewicz A, Leszczynska-Rodziewicz A, Permoda A et al. Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiatry 2005; 38: 166–170.

    Article  CAS  PubMed  Google Scholar 

  93. Rybakowski JK, Borkowska A, Skibinska M, Hauser J . Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. Mol Psychiatry 2006; 11: 122–124.

    Article  CAS  PubMed  Google Scholar 

  94. Rybakowski JK, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P, Leszczynska-Rodziewicz A et al. Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain-derived neurotrophic factor gene. Psychiatry Clin Neurosci 2006; 60: 70–76.

    Article  CAS  PubMed  Google Scholar 

  95. Shimizu E, Hashimoto K, Koizumi H, Kobayashi K, Itoh K, Mitsumori M et al. No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 708–712.

    Article  CAS  PubMed  Google Scholar 

  96. Tramontina J, Frey BN, Andreazza AC, Zandona M, Santin A, Kapczinski F . Val66met polymorphism and serum brain-derived neurotrophic factor levels in bipolar disorder. Mol Psychiatry 2007; 12: 230–231.

    Article  CAS  PubMed  Google Scholar 

  97. Tsai SJ, Liao DL, Yu YW, Chen TJ, Wu HC, Lin CH et al. A study of the association of (Val66Met) polymorphism in the brain-derived neurotrophic factor gene with alcohol dependence and extreme violence in Chinese males. Neurosci Lett 2005; 381: 340–343.

    Article  CAS  PubMed  Google Scholar 

  98. Groves JO . Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007; 12: 1079–1088.

    Article  CAS  PubMed  Google Scholar 

  99. Post RM . Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res 2007; 41: 979–990.

    Article  PubMed  Google Scholar 

  100. Schule C, Zill P, Baghai TC, Eser D, Zwanzger P, Wenig N et al. Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients. Psychoneuroendocrinology 2006; 31: 1019–1025.

    Article  PubMed  CAS  Google Scholar 

  101. Sen S . Identifying genetic variants associated with the personality trait neuroticism, a marker for depression. Dissertation Abstr Int:Section-B:Sciences Engineering 2005; 66 [2-B]: 749.

    Google Scholar 

  102. Strauss J, Barr CL, George CJ, Ryan CM, King N, Shaikh S et al. BDNF and COMT polymorphisms: relation to memory phenotypes in young adults with childhood-onset mood disorder. Neuromolecular Med 2004; 5: 181–192.

    Article  CAS  PubMed  Google Scholar 

  103. Tsai SJ . Increased central brain-derived neurotrophic factor activity could be a risk factor for substance abuse: Implications for treatment. Med Hypotheses 2007; 68: 410–414.

    Article  CAS  PubMed  Google Scholar 

  104. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006; 59: 673–680.

    Article  CAS  PubMed  Google Scholar 

  106. Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 2007; 62: 423–428.

    Article  CAS  PubMed  Google Scholar 

  107. Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ et al. Genetic association study of BDNF in depression: Finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 814–821.

    Article  CAS  PubMed  Google Scholar 

  108. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P et al. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 2005; 26: 115–123.

    Article  CAS  PubMed  Google Scholar 

  109. Tan YL, Zhou DF, Zhang XY . Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements. Schizophr Res 2005; 74: 263–270.

    Article  PubMed  Google Scholar 

  110. Zubenko GS, Hughes III HB, Stiffler JS, Brechbiel A, Zubenko WN, Maher BS et al. Sequence variations in CREB1 cosegregate with depressive disorders in women. Mol Psychiatry 2003; 8: 611–618.

    Article  CAS  PubMed  Google Scholar 

  111. Brown GW, Harris T . Life-events and depression. The Social Origins of Depression; A study of Psychiatric Disorder in Women. Tavistocj Publications: London, 1978, pp 100–116.

    Google Scholar 

  112. Kessler RC . The effects of stressful life events on depression. Annu Rev Psychol 1997; 48: 191–214.

    Article  CAS  PubMed  Google Scholar 

  113. Paykel ES . Life events and affective disorders. Acta Psychiatr Scand Suppl 2003; 61–66.

    Article  Google Scholar 

  114. Becker JB, Monteggia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R et al. Stress and disease: is being female a predisposing factor? J Neurosci 2007; 27: 11851–11855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kessler RC, McLeod JD . Sex differences in vulnerability to life events. Am Sociol Rev 1984; 49: 620–631.

    Article  Google Scholar 

  116. Troisi A . Gender differences in vulnerability to social stress: a Darwinian perspective. Physiol Behav 2001; 73: 443–449.

    Article  CAS  PubMed  Google Scholar 

  117. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.

    Article  CAS  PubMed  Google Scholar 

  118. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B . The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005; 62: 529–535.

    Article  CAS  PubMed  Google Scholar 

  119. Uher R, McGuffin P . The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry 2008; 13: 131–146.

    Article  CAS  PubMed  Google Scholar 

  120. Sjoberg RL, Nilsson KW, Nordquist N, Ohrvik J, Leppert J, Lindstrom L et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006; 9: 443–449.

    Article  PubMed  CAS  Google Scholar 

  121. Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P et al. Gene–environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 2004; 9: 908–915.

    Article  CAS  PubMed  Google Scholar 

  122. Cahill L . Why sex matters for neuroscience. Nat Rev Neurosci 2006; 7: 477–484.

    Article  CAS  PubMed  Google Scholar 

  123. Madeira MD, Lieberman AR . Sexual dimorphism in the mammalian limbic system. Prog Neurobiol 1995; 45: 275–333.

    Article  CAS  PubMed  Google Scholar 

  124. Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness Jr VS et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex 2001; 11: 490–497.

    Article  CAS  PubMed  Google Scholar 

  125. McEwen BS . The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000; 886: 172–189.

    Article  CAS  PubMed  Google Scholar 

  126. Smith MA, Makino S, Kvetnansky R, Post RM . Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995; 15: 1768–1777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS . Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 2002; 22: 3251–3261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM . Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 1997; 56: 131–137.

    Article  CAS  PubMed  Google Scholar 

  129. Eisch AJ, Bolanos CA, de WJ, Simonak RD, Pudiak CM, Barrot M et al. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 2003; 54: 994–1005.

    Article  CAS  PubMed  Google Scholar 

  130. Compton III WM, Helzer JE, Hwu HG, Yeh EK, McEvoy L, Tipp JE et al. New methods in cross-cultural psychiatry: psychiatric illness in Taiwan and the United States. Am J Psychiatry 1991; 148: 1697–1704.

    Article  PubMed  Google Scholar 

  131. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M . ‘Vascular depression’ hypothesis. Arch Gen Psychiatry 1997; 54: 915–922.

    Article  CAS  PubMed  Google Scholar 

  132. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF et al. Hippocampal volume in geriatric depression. Biol Psychiatry 2000; 48: 301–309.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all authors included in the studies for their cooperation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B Franke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verhagen, M., van der Meij, A., van Deurzen, P. et al. Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatry 15, 260–271 (2010). https://doi.org/10.1038/mp.2008.109

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.109

Keywords

This article is cited by

Search

Quick links