SEARCH

SEARCH BY CITATION

Keywords:

  • brain-derived neurotrophic factor;
  • meta-analysis;
  • schizophrenia

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Brain-derived neurotrophic factor (BDNF) has been suggested to play a role in the pathophysiology of schizophrenia. The C270T polymorphism (rs56164415) in the BDNF 5′-non-coding region has been extensively investigated for an association with schizophrenia, but with conflicting results. An updated meta-analysis was therefore performed of 13 case–control association studies (3505 patients and 3992 controls). An association was found between the T allele and schizophrenia. The association was significant in the East Asian population, but not in the Caucasian population. It is suggested that the BDNF C270T polymorphism contributes to schizophrenia susceptibility, especially in East Asian subjects.

BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) regulates neuronal growth and synaptic plasticity.[1] Several studies have reported altered BDNF levels in the brain and blood of schizophrenia patients.[1] These findings suggest that BDNF plays a role in the pathophysiology of schizophrenia.[1]

The C270T polymorphism (rs56164415) in the BDNF 5′-non-coding region[2] has been extensively investigated for an association with schizophrenia, but with conflicting results.[3-14] In the most recent meta-analysis, there was a significant association between the T allele and schizophrenia in a fixed-effect model, but not in a random-effect model.[13] In addition, the association in the fixed-effect model did not remain significant after omission of the study by Szekeres et al.[4] In the SZGene meta-analysis (http://www.szgene.org/meta.asp?geneID=2), the association was not significant. Thus, the true nature of the association between C270T and schizophrenia remains to be determined. To assess whether the BDNF C270T polymorphism confers increased susceptibility to schizophrenia, an updated meta-analysis was performed.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We included 13 case–control association studies of the BDNF C270T polymorphism with schizophrenia in the meta-analysis. We asked the correspondence authors for the genotype counts of C270T if those were not available in the publications,[11, 15] or if there was a typographical error in how these were reported.[6] We assessed the Hardy–Weinberg equilibrium (HWE) in the patients and controls of each study using Haploview v4.2 (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). We performed fixed- and random-effect model meta-analyses using Catmap (http://cran.r-project.org/src/contrib/Archive/catmap/). Publication bias was assessed using a linear regression analysis to measure funnel plot asymmetry. P < 0.05 was considered to indicate statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The genotype distributions did not deviate significantly from HWE in either group in all studies (data not shown), except for the control group of Sun et al. (P = 0.048).[14] In both fixed- and random-effect models, the T allele was significantly associated with schizophrenia (Table 1), and the combined odds ratios remained significant after the sequential omission of individual studies (data not shown). In both models, the association was significant in the East Asian population, but not in the Caucasian population. Linear regression analysis showed no significant funnel plot asymmetry.

Table 1. BDNF C270T polymorphism and schizophrenia: Meta-analysis of case–control studies
StudyEthnicityPatientsControlsC vs T allele
nCTnCTOR95% CIP
  1. Q = 14.6, d.f. = 12, P = 0.266 for heterogeneity; t = 2.07, d.f. = 11, P = 0.063 for publication bias. Q = 6.11, d.f. = 5, P = 0.296 for heterogeneity; t = 1.40, d.f. = 4, P = 0.235 for publication bias. §Q = 8.28, d.f. = 6, P = 0.219 for heterogeneity; t = 2.28, d.f. = 5, P = 0.071 for publication bias. BDNF, brain-derived neurotrophic factor; CI, confidence interval; OR, odds ratio.

Nanko et al. (2003)[3]Japanese17833917332649152.171.07–4.400.028
Szekeres et al. (2003)[4]Hungarian101174286813245.311.82–15.510.001
Anttila et al. (2005)[5]Finnish941711798182141.290.62–2.700.495
Galderisi et al. (2005)[6]Italian10619913111211111.250.55–2.860.592
Szczepankiewicz et al. (2005)[7]Polish39775539380725351.070.67–1.710.777
Jönsson et al. (2006)[8]Swedish18735420275521291.020.57–1.820.960
Watanabe et al. (2006)[9]Japanese34967226423827191.680.92–3.070.086
Zhang et al. (2006)[10]European American8415810250470300.990.47–2.070.982
Li et al. (2007)[11]Han Chinese1302461414427991.760.75–4.150.188
Xu et al. (2007)[12]Han Chinese27553416297574200.860.44–1.680.658
Kawashima et al. (2009)[13]Japanese111521597111022138661.070.76–1.500.716
Zai et al. (2010)[15]European Canadian16631418166316161.130.57–2.260.725
Sun et al. (2011)[14]Han Chinese32360640346661311.410.87–2.280.163
All (fixed) 3505  3992  1.251.06–1.480.007
All (random)       1.281.06–1.540.011
Asian (fixed) 2370  2644  1.291.04–1.600.021
Asian (random)       1.321.03–1.700.029
Caucasian (fixed)§ 1135  1348  1.200.93–1.550.157
Caucasian (random)§       1.240.91–1.680.176

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The conflicting findings of earlier association studies between the BDNF C270T polymorphism and schizophrenia may have been a result of insufficient statistical power in individual studies. The most recent meta-analysis did not yield clear evidence for the association.[13] The present updated meta-analysis provides the most comprehensive assessment to date of the association. In the present updated meta-analysis, the T allele was found to be associated with schizophrenia. The significance of this association was not influenced by any single study. Stratification of the studies by ethnicity indicated that the T allele was associated with schizophrenia in the East Asian population, but not in the Caucasian population. This finding may be explained by genetic heterogeneity between these two populations. Indeed, there was a difference in the mean frequency of T allele between the East Asian (0.031) and Caucasian (0.051) populations. Notably, a recent exploratory analysis reported that the T allele was associated with a higher prevalence of neuropsychiatric symptoms and specifically with the presence of hallucinations in patients with Alzheimer's disease.[16] Taken together, the T allele may predispose to schizophrenia, as well as psychotic symptoms of psychiatric disorders. The functional implications of the BDNF C270T polymorphism are still unclear, however, and should be clarified in future studies. In conclusion, the present updated meta-analysis provides evidence for the contribution of the BDNF C270T polymorphism to schizophrenia susceptibility, especially in East Asian subjects.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

We thank the authors who kindly provided the data necessary for our meta-analysis. There is no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Favalli G, Li J, Belmonte-de-Abreu P, Wong AH, Daskalakis ZJ. The role of BDNF in the pathophysiology and treatment of schizophrenia. J. Psychiatr. Res. 2012; 46: 111.
  • 2
    Kunugi H, Ueki A, Otsuka M et al. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol. Psychiatry 2001; 6: 8386.
  • 3
    Nanko S, Kunigi H, Hirasawa H, Kato N, Nabika T, Kobayashi S. Brain-derived neurotrophic factor gene and schizophrenia: Polymorphism screening and association analysis. Schizophr. Res. 2003; 62: 281283.
  • 4
    Szekeres G, Juhász A, Rimanóczy Á, Kéri S, Janka Z. The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr. Res. 2003; 65: 1518.
  • 5
    Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J. Neural Transm. 2005; 112: 885890.
  • 6
    Galderisi S, Maj M, Kirkpatrick B et al. COMT Val158Met and BDNF C270T polymorphisms in schizophrenia: A case-control study. Schizophr. Res. 2005; 73: 2730.
  • 7
    Szczepankiewicz A, Skibinska M, Czerski PM et al. No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. Schizophr. Res. 2005; 76: 187193.
  • 8
    Jönsson EG, Edman-Ahlbom B, Sillén A et al. Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: An association study. Prog. Neuropsychopharmacol. Biol. Psychiatry 2006; 30: 924933.
  • 9
    Watanabe Y, Muratake T, Kaneko N, Nunokawa A, Someya T. No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr. Res. 2006; 84: 2935.
  • 10
    Zhang H, Ozbay F, Lappalainen J 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: 387393.
  • 11
    Li W, Wei J, Zhou DF et al. Lack of association between the BDNF C270T polymorphism and schizophrenia in a Chinese Han population. Schizophr. Res. 2007; 97: 297298.
  • 12
    Xu M-Q, St Clair D, Ott J, Feng G-Y, He L. Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: A moderate-scale population-based study and meta-analysis. Schizophr. Res. 2007; 91: 613.
  • 13
    Kawashima K, Ikeda M, Kishi T et al. BDNF is not associated with schizophrenia: Data from a Japanese population study and meta-analysis. Schizophr. Res. 2009; 112: 7279.
  • 14
    Sun RF, Zhu YS, Kuang WJ, Liu Y, Li SB. The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia. Neurosci. Lett. 2011; 489: 3437.
  • 15
    Zai CC, Manchia M, De Luca V et al. Association study of BDNF and DRD3 genes in schizophrenia diagnosis using matched case-control and family based study designs. Prog. Neuropsychopharmacol. Biol. Psychiatry 2010; 34: 14121418.
  • 16
    Zdanys KF, Kleiman TG, Zhang H et al. BDNF variants, premorbid educational attainment, and disease characteristics in Alzheimer's disease: An exploratory study. J. Alzheimers Dis. 2009; 17: 887898.