Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: An association study

https://doi.org/10.1016/j.pnpbp.2006.02.008Get rights and content

Abstract

Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been suggested to be associated with schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 187) and control subjects (n = 275) were assessed for four BDNF gene polymorphisms. There were no significantly different allele, genotype or haplotype frequencies between cases or controls. Neither were there any differences when schizophrenic patients were sub-divided with regard to a number of different clinical variables, although a small group of psychotic patients with prominent affective features displayed higher frequencies of the less common alleles of the Val66Met and 11757 G/C polymorphisms compared to controls. The present Swedish results do not verify previous associations between putative functional BDNF gene polymorphisms and schizophrenia. However, when combined with previous studies meta-analyses indicated that the BDNF 270 T-allele and the Val66Met homozygous state were associated with the disorder. Thus, the BDNF gene may confer susceptibility to schizophrenia. Additional studies are warranted to shed further light on this possibility.

Introduction

The aetiology of schizophrenia remains unknown, despite a century of accelerating research. A number of different aetiopathological hypotheses have been advocated, and the complexity of these has increased over the last years (Kornhuber et al., 2004). Based on studies of pre-schizophrenic individuals and brain anatomy schizophrenia has been suggested to be neurodevelopmental in origin (Jones and Murray, 1991, McClure and Lieberman, 2003, Mjellem and Kringlen, 2001, Weinberger, 1995). There is also evidence that neurodegenerative mechanisms are involved in schizophrenia, and hypotheses taking both these aspects into account have been put forward (Ashe et al., 2001). Alterations in monoamine transmission have since long been hypothesised in the pathophysiology of schizophrenia (van Kammen and Kelley, 1991, van Rossum, 1967, Woolley and Shaw, 1954). Recent extensions of the dopamine hypothesis of schizophrenia suggest interactions with the other monoamines as well as other neurotransmitters (Carlsson et al., 2001). Brain-derived neurotrophic factor (BDNF) regulates survival, differentiation, morphology and synaptic remodelling of neurons (Ashe et al., 2001). BDNF has also been shown to modulate transmitter synthesis, metabolism and release, postsynaptic ion channel fluxes, neuronal activity and long term potentiation (Ashe et al., 2001). For instance, BDNF is involved in the development and survival of dopaminergic and serotonergic neurons (Eaton et al., 1995, Spenger et al., 1995, Studer et al., 1995, Zhou et al., 1994a, Zhou et al., 1994b). Elevated BDNF mRNA levels have been reported in the hippocampus and anterior cingulate cortex of brains from schizophrenia patients (Takahashi et al., 2000). Higher BDNF concentrations have been reported in hippocampus and cortical areas of patients with schizophrenic psychosis than in control subjects (Durany et al., 2001). Reduced BDNF levels were reported in serum of schizophrenic patients in some (Pirildar et al., 2004, Tan et al., 2005b, Toyooka et al., 2002) but not all studies (Shimizu et al., 2003). Another study reported elevated serum BDNF concentrations in cannabis-using schizophrenic patients but not among patients not using this drug (Jockers-Scherübl et al., 2004). In an animal model of schizophrenia altered expression of the BDNF gene was reported (Molteni et al., 2001).

Family, twin and adoption studies suggest that genetic factors play a role in the aetiology of schizophrenia (McGuffin et al., 1995). Thus, the BDNF gene, located on chromosome 11p13 (Hanson et al., 1992, Maisonpierre et al., 1991), is a putative candidate gene for schizophrenia taking aspects of the neurodevelopmental, neurodegenerative as well as the monoamine hypotheses into account.

Previous studies testing associations between BDNF gene variants and schizophrenia have produced contradictory results. In the analyses of a BDNF dinucleotide-repeat variant in the 5′-end between patients and controls, or the transmission from parents to ill children, only one study reported association (Muglia et al., 2003). Eight other studies did not find evidence for association or linkage (Fanous et al., 2004, Hawi et al., 1998, Krebs et al., 2000, Neves-Pereira et al., 2005, Sasaki et al., 1997, Schumacher et al., 2005, Virgos et al., 2001, Wassink et al., 1999). However, this BDNF dinucleotide-repeat has recently been reported to be built up by three different and continuous dinucleotide-repeats, casting doubts on the original investigations (Koizumi et al., 2005). Researchers from Japan and Hungary reported association between another recently discovered variant (270 C/T) in the 5′ upstream region and schizophrenia (Nanko et al., 2003, Szekeres et al., 2003). Interestingly, there are also reports of association between a third BDNF variant, Val66Met, and schizophrenia (Hong et al., 2003b, Neves-Pereira et al., 2005). This is of interest as this polymorphism has been reported to be associated with altered hippocampal activation and volume in healthy subjects and schizophrenic patients (Egan et al., 2003, Szeszko et al., 2005). However, a number of studies have not been able to detect association between 270 C/T or Val66Met polymorphisms and schizophrenia (Anttila et al., 2004, de Krom et al., 2005, Egan et al., 2003, Galderisi et al., 2005, Nanko et al., 2003, Schumacher et al., 2005, Skibinska et al., 2004, Szczepankiewicz et al., 2005). The Val66Met polymorphism has also been associated with bipolar disorder in several (Geller et al., 2004, Lohoff et al., 2005, Neves-Pereira et al., 2002, Sklar et al., 2002) but not all Caucasian samples (Neves-Pereira et al., 2005, Oswald et al., 2004, Schumacher et al., 2005, Skibinska et al., 2004). Studies in Asian subjects did not report association (Hong et al., 2003a, Kunugi et al., 2004, Nakata et al., 2003).

In the present study we investigated several BDNF variants in schizophrenic patients and control subjects from Sweden. We also performed meta-analysis including the present and previous case-control data, in order to position the present Swedish replication attempt in the context of previous reports.

Section snippets

Subjects

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Karolinska Hospital. All subjects participated after giving informed consent.

Subjects were unrelated Caucasian individuals living in the north-western part of Stockholm County and have been previously described (Jönsson et al., 2003). Subjects could be allocated into two groups. The first group has been previously described and investigated in several reports (Jönsson et al., 1993,

Swedish sample

There were 187 schizophrenic patients (62.6% men, mean age ± standard deviation 44.3 ± 15.8 years) and 275 controls (62.9% men, 40.5 ± 9.8 years). Although the gender ratio was not significantly different between cases and controls, patients were older than controls (t = 3.194, degree of freedom [df] = 457, p = 0.002). Probands' and parish register's report of parents' or grandparents' birthplaces suggested no significant difference in the national ancestry of cases and controls.

Three of the investigated

Discussion

In the present study no robust significant differences were found when schizophrenic patients and control subjects were compared for four BDNF polymorphisms. This is at variance with some previous results (Hong et al., 2003b, Nanko et al., 2003, Neves-Pereira et al., 2005, Szekeres et al., 2003), although in accordance with most studies (Table 5, Table 6).

Two studies, analysing the 270 C/T variant, reported association to schizophrenia with the T-allele in Japanese and Hungarian samples (Nanko

Conclusions

No significant robust association was found between four BDNF gene polymorphisms and schizophrenia. Standing alone, the present results cast further doubts about the involvement of these BDNF gene polymorphisms in schizophrenia. However, when analysed together with previous reports evidence for association with the disorder is still present. This calls for further studies with larger populations.

Acknowledgements

This study was supported by the Swedish Research Council (3560 + K2004-21X-15078-01A), National Institute of Mental Health (NIMH; 44814), Söderström-Königska Foundation, Wallenberg Foundation, and the HUBIN project. We thank Alexandra Tylec, Emma Bonnet, Lilian Frygnell, Monica Hellberg, and Kjerstin Lind for technical assistance. We thank Mariken de Krom and Marie-Odile Krebs for giving access to genotype data from their studies.

References (87)

  • M.C. Jockers-Scherübl et al.

    Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse

    Neurosci Lett

    (2004)
  • H. Kunugi 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)
  • P.C. Maisonpierre et al.

    Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations

    Genomics

    (1991)
  • P. McGuffin et al.

    Genetic basis of schizophrenia

    Lancet

    (1995)
  • K. Meszaros et al.

    Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special?

    Psychiatry Res

    (2000)
  • K. Nakata et al.

    Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder

    Neurosci Lett

    (2003)
  • M. Neves-Pereira et al.

    The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study

    Am J Hum Genet

    (2002)
  • G. Oxenstierna et al.

    Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals—a genetic study

    J Psychiatr Res

    (1986)
  • G. Oxenstierna et al.

    Increased frequency of abberant CSF circulation in schizophrenic patients compared to healthy volunteers

    Eur Psychiatry

    (1996)
  • S. Pirildar et al.

    Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment

    Prog Neuropsychopharmacol Biol Psychiatry

    (2004)
  • J. Schumacher et al.

    Evidence for a relationship between genetic variants at the Brain-Derived Neurotrophic Factor (BDNF) locus and major depression

    Biol Psychiatry

    (2005)
  • E. Shimizu et al.

    Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls

    Neurosci Lett

    (2003)
  • M. Stephens et al.

    A comparison of Bayesian methods for haplotype reconstruction from population genotype data

    Am J Hum Genet

    (2003)
  • A. Szczepankiewicz et al.

    No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia

    Schizophr Res

    (2005)
  • G. Szekeres et al.

    The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia

    Schizophr Res

    (2003)
  • Y.L. Tan et al.

    Effect of the BDNF Val66Met genotype on episodic memory in schizophrenia

    Schizophr Res

    (2005)
  • Y.L. Tan et al.

    Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics

    Neurosci Lett

    (2005)
  • K. Toyooka et al.

    Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients

    Psychiatry Res

    (2002)
  • D.P. van Kammen et al.

    Dopamine and norepinephrine activity in schizophrenia. An integrative perspective

    Schizophr Res

    (1991)
  • C. Virgos et al.

    Association study of schizophrenia with polymorphisms at six candidate genes

    Schizophr Res

    (2001)
  • D.R. Weinberger

    From neuropathology to neurodevelopment

    Lancet

    (1995)
  • J. Zhou et al.

    The response of human and rat fetal ventral mesencephalon in culture to the brain-derived neurotrophic factor treatment

    Brain Res

    (1994)
  • J. Zhou et al.

    The stimulatory effect of brain-derived neurotrophic factor on dopaminergic phenotype expression of embryonic rat cortical neurons in vitro

    Brain Res Dev Brain Res

    (1994)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (1987)
  • American Psychiatric Association

    Diagnostic and statistical manual of mental disorders

    (1995)
  • S. Anttila et al.

    Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics

    J Neural Transm

    (2004)
  • J.C. Barrett et al.

    Haploview: analysis and visualization of LD and haplotype maps

    Bioinformatics

    (2005)
  • A. Carlsson et al.

    Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence

    Annu Rev Pharmacol Toxicol

    (2001)
  • J. Cohen

    Statistical power analysis for the behavioral sciences

    (1988)
  • T.J. Crow

    Nature of the genetic contribution to psychotic illness—a continuum viewpoint

    Acta Psychiatr Scand

    (1990)
  • M. Damberg et al.

    Transcription factor AP-2b genotype, striatal dopamine D2 receptor density and cerebrospinal fluid monoamine metabolite concentrations in humans

    J Neural Transm

    (2004)
  • M. de Krom et al.

    Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients

    Psychiatr Genet

    (2005)
  • B. Ekholm et al.

    Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses

    Nord J Psychiatry

    (2005)
  • Cited by (0)

    View full text