The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients

https://doi.org/10.1016/j.pnpbp.2010.04.019Get rights and content

Abstract

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Recent studies have reported that the Val66Met polymorphism of the BDNF gene may be associated with susceptibility for schizophrenia and age of onset of this disease, with mix results. In the present study, the BDNF Val66Met gene polymorphism was examined in 387 inpatients (259 men and 128 women) meeting the DSM-IV criteria for schizophrenia and unrelated 365 healthy controls (255 men and 110 women). The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS). Age of onset was defined as the age at which the psychotic symptoms first appeared. Our results showed that genotype frequency distributions and allelic frequencies did not differ between patients and controls. No interaction was found between sex and genotypes. Analysis of covariance (ANCOVA) showed a significance of the BDNF Val66Met genotypes on the age of onset (F = 3.76, p < 0.02), after adjusting sex, age and duration of illness. Furthermore, ANCOVA showed that the significance of the BDNFVal66Met genotypes on age of onset was increased comparing the Val66Met heterozygotes with the combination of Val66Val and Met66Met homozygotes (F = 5.85, p < 0.01). Our results suggest that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia, but to the onset of the disease. Furthermore, our results show the heterozygous effect of the BDNF Val66Met gene on the clinical variability of schizophrenia phenotype.

Introduction

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, not only regulates cell survival, proliferation, and synaptic growth in the developing central nervous system (CNS), but also is a critical element in modulating synaptic changes and brain plasticity (Poo, 2001, Tyler et al., 2002, Egan et al., 2003). Converging lines of evidence suggest that BDNF could be implicated in the neurodevelopmental abnormalities found in schizophrenia brain (Nawa et al., 2000). Recent studies indicate that a single nucleotide polymorphism (rs6265) producing a nonconservative amino acid substitution (valine to methionine) in the 5′-precusor peptide (pro-BDNF) at codon 66 (Val66Met) has been shown to dramatically alter the intracellular trafficking and packaging of pro-BDNF and, thus, regulate secretion of the mature peptide (Egan et al., 2003). Two studies reported that the Val66Met polymorphism of the BDNF gene was associated with susceptibility for schizophrenia (Neves-Pereira et al., 2005, Rosa et al., 2006). However, several studies did not replicate the result (Naoe et al., 2007, Xu et al., 2007, Varnäs et al., 2008). The most recent meta-analysis results provided no evidence of association between Val66Met polymorphism and schizophrenia, and large heterogeneity between studies (Kanazawa et al., 2007, Zintzaras, 2007).

Two recent studies in Japanese (Numata et al., 2006) and African–American cohort (Chao et al., 2008) show that the BDNF Val66Met polymorphism is associated with age of onset of schizophrenia; however, other studies in Caucasian populations have not observed a similar association (Gourion et al., 2005, Naoe et al., 2007). It was thought important to replicate the work with a different ethnic population to rule out a false positive result from ethnic differences in the frequency distribution of the DNA marker or from the population structure. The present work was therefore undertaken to investigate whether the BDNF Val66Met polymorphism was associated with susceptibility for schizophrenia and onset of this disease in ethnically homogeneous samples of Chinese Han population.

Section snippets

Subjects

Three hundred and eighty-seven physically healthy patients (male/female = 259/128) who met DSM-IV for schizophrenia and unrelated 365 healthy controls (255 men and 110 women) were included in the study. All schizophrenic patients were recruited from among the inpatients of Beijing Hui-Long-Guan Hospital, a Beijing City owned psychiatric hospital. Diagnoses were made for each patient by two independent experienced psychiatrists. All schizophrenic patients were of the chronic type, with duration of

Results

Table 1 shows the characteristics of the subjects in the schizophrenia and normal controls. There were no significant differences in sex, age, education and BMI between two groups (all p > 0.05). Allele frequencies, genotype distributions and the statistical analysis are shown in Table 2. Genotype distributions had no deviation from Hardy–Weinberg equilibrium in both groups (p > 0.05). There was no significant difference in frequency of alleles of BDNF in schizophrenia and normal controls (χ2 = 0.09,

Discussion

Our results demonstrate that the BDNF Val66Met polymorphism may not contribute directly to the susceptibility to schizophrenia. This polymorphism however is associated with age of onset of schizophrenia, which is consistent with two previous studies in Japanese (Numata et al., 2006) and African–American cohort (Chao et al., 2008), although some other studies have not found a similar association in Caucasian population (Gourion et al., 2005, Naoe et al., 2007). Thus, the association between the

Acknowledgments

This study was supported by grants from the Stanley Medical Research Institute (03T-459 and 05T-726), and the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education, and Clinical Center, United States National Institute of Health K05-DA0454, P50-DA18827, and U01-MH79639.

References (26)

  • E. Dempster et al.

    Association between BDNF Val66 Met genotype and episodic memory

    Am J Med Genet B Neuropsychiatr Genet

    (2005)
  • D. Gourion et al.

    Age at onset of schizophrenia: interaction between brain-derived neurotrophic factor and dopamine D3 receptor gene variants

    NeuroReport

    (2005)
  • A.R. Hariri et al.

    Brain-derived neurotrophic factor Val66Met polymorphism affects human memory-related hippocampal activity and predicts memory performance

    J Neurosci

    (2003)
  • Cited by (32)

    • Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis

      2022, Neurologia
      Citation Excerpt :

      There are 108 possibly eligible articles selected that are related to the objective of this research. The study flow diagram shows that only 2526–28,34–55 articles were considered based on the eligibility criteria (Fig. 1). All selected studies were evaluated using HWE and NOS.

    • Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: Pathophysiological and phenotypic implications

      2017, Schizophrenia Research
      Citation Excerpt :

      To the best of our knowledge, this is the first report to examine the discriminatory performance of oxidative stress and immune-inflammatory markers as well as MMP-9 in distinguishing SZ patients from healthy controls. Converging lines of proof suggested that genetic determinants, such as the reported MMP-9 − 1562C > T (Bienkowski et al., 2015; Groszewska et al., 2011; Han et al., 2011; Rybakowski et al., 2009) and BDNF 196G > A SNPs (Golimbet et al., 2008; Lu et al., 2012; Skibinska et al., 2008; Zakharyan et al., 2011; Zhang et al., 2012; Zhou et al., 2010), may be associated with SZ. However, findings of earlier studies on the relationship of these SNPs with SZ are opposing and it has not been definitively figured out which of these SNPs associates with SZ.

    • BDNF polymorphisms are associated with schizophrenia onset and positive symptoms

      2016, Schizophrenia Research
      Citation Excerpt :

      A possible explanation for this inconsistency is a difference in ethnic background. For example, the Met allele frequency of this polymorphism in Chinese (around 50%) (Zhou et al., 2010; Yi et al., 2011) is notably different from that in Caucasian subjects (around 20%) (Naoe et al., 2007; Varnas et al., 2008). Thus, interethnic differences in the genotype frequencies of the BDNF Val66Met polymorphism may play an important role in accounting for the inconsistent results across the different populations.

    View all citing articles on Scopus
    1

    These three authors (Dong Hao Zhou, Quan Zhi Yan, and Xiao Mei Yan) contributed equally to the study.

    View full text