No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population

https://doi.org/10.1016/j.schres.2006.03.011Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case–control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations.

Introduction

Cytokines and growth factors may be implicated in the etiology or pathology of schizophrenia (for a review: Nawa et al., 2000). However, the pathogenesis of schizophrenia currently remains unclear. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which also includes nerve growth factor and neurotrophin-3. BDNF supports the survival and differentiation of several types of neurons, such as dopaminergic and GABAergic neurons (Knüsel et al., 1991, Mizuno et al., 1994), and has also been implicated in the types of synaptic plasticity associated with long-term potentiation (Korte et al., 1995) and spatial memory (Mizuno et al., 2000). Postmortem studies on brains from schizophrenia patients have revealed changes in the BDNF protein or mRNA expression levels, although these observations remain controversial (Takahasi et al., 2000, Chen et al., 2001, Durany et al., 2001, Iritani et al., 2003, Weickert et al., 2003, Knable et al., 2004, Hashimoto et al., 2005). Furthermore, several studies reported decreased serum BDNF levels in schizophrenia patients (Toyooka et al., 2002, Pırıldar et al., 2004, Tan et al., 2005b, Tan et al., 2005c), whereas other studies failed to find such decreases (Shimizu et al., 2003, Jockers-Scherübl et al., 2004). Nevertheless, these findings suggest that BDNF is likely to be related to the pathogenesis of schizophrenia.

Genetic variants in the BDNF gene, located on chromosome 11p13, have also been tested for their associations with schizophrenia. Specifically, the most extensively investigated BDNF gene polymorphisms are as follows: the (GT)n dinucleotide repeat in the promoter region; rs6265 (G196A) producing an amino acid substitution (valine to methionine) at codon 66; and C132T (formerly designated C270T; Kunugi et al., 2001, Itoh et al., 2005) in the 5′-noncoding region. Muglia et al. (2003) demonstrated biased transmission of the (GT)n alleles from parents to schizophrenia probands. Neves-Pereira et al. (2005) found that the G allele frequency of rs6265 was significantly higher in schizophrenia patients than in control subjects, while Rosa et al. (2006) reported that the G allele was preferentially transmitted from parents to affected offspring. Interestingly, this polymorphism was associated with episodic memory (Egan et al., 2003, Dempster et al., 2005, Tan et al., 2005a) and hippocampal volume (Szeszko et al., 2005), suggesting that rs6265 may be functional. Recently, Schumacher et al. (2005) demonstrated that the haplotype constructed from rs988748-(GT)n-rs6265 was associated with schizophrenia. In addition, Nanko et al. (2003) and Szekeres et al. (2003) detected an association between the C132T polymorphism and schizophrenia. However, contradictory negative results have also been reported for (GT)n (Sasaki et al., 1997, Hawi et al., 1998, Wassink et al., 1999, Krebs et al., 2000, Virgos et al., 2001, Fanous et al., 2004, Neves-Pereira et al., 2005), rs6265 (Egan et al., 2003, Hong et al., 2003, Anttila et al., 2005, de Krom et al., 2005, Dempster et al., 2005, Gourion et al., 2005, Szeszko et al., 2005, Tan et al., 2005a, Chen et al., 2006) and C132T (Anttila et al., 2005, Galderisi et al., 2005, Szczepankiewicz et al., 2005), and these inconsistencies require further investigation. Therefore, we performed a case–control association study in Japanese subjects to assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia. We did not investigate the (GT)n dinucleotide repeat, since Sasaki et al. (1997) reported that this repeat was not associated with schizophrenia in Japanese and that the variation was much less polymorphic in Japanese subjects than in Caucasian subjects.

Section snippets

Subjects

The study population consisted of 349 schizophrenia patients (187 males and 162 females; mean age, 41.4 [SD 15.0] years) and 423 control subjects (217 males and 206 females: mean age, 34.2 [SD 7.7] years). All participants were unrelated Japanese living in Niigata Prefecture or Fukushima Prefecture. Patients meeting the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria for schizophrenia were recruited from the following 14 hospitals: Iizuka Hospital, Kohdo

Results

Table 1 shows the genotype and allele frequencies of the three SNPs in the BDNF gene among the patients and control subjects. The genotype frequencies of all three SNPs in both groups did not differ significantly from the values expected from HWE (p > 0.05). The genotype and allele frequencies of rs98874 and rs6265 in the patients did not differ from those in the control subjects (p > 0.05). Regarding the C132T polymorphism, there was a trend toward a higher frequency of the C/T genotype in

Discussion

In the present study, we found no significant association between three BDNF gene polymorphisms (rs988748, C132T and rs6265) and schizophrenia in our Japanese subjects. Neves-Pereira et al. (2005) found that the G allele frequency for rs6265 was significantly higher in schizophrenia patients than in control subjects, while Rosa et al. (2006) reported that the G allele was preferentially transmitted from parents to affected offspring. However, other studies, including the present study, failed

Acknowledgements

The authors thank the patients, the patients' families and the healthy volunteers for their participation; and Hiroshi Kusano and Tomoko Yamada for excellent technical assistance. This work was supported by Health and Labour Sciences Research Grants for Research on the Human Genome, Tissue Engineering Food Biotechnology (to T.S.), Health and Labour Sciences Research Grants for Research on Psychiatric and Neurological Diseases and Mental Health (to T.S.), a Grant from the Research Group For

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