Brain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia

doi:10.1016/j.biopsych.2006.08.025

Biological Psychiatry

Volume 61, Issue 7, 1 April 2007, Pages 911-922

https://doi.org/10.1016/j.biopsych.2006.08.025 Get rights and content

Background

There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders.

Methods

We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others.

Results

The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state.

Conclusions

The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.

Section snippets

Search Strategy

The Medline database was searched using the PubMed search engine. This database was searched from the first date available up to May 17, 2006, using as a first step the following combination of key words: polymorph* AND (bdnf or brain derived), mutation AND (bdnf or brain derived), variant* AND (bdnf or brain derived), associat* AND (bdnf or brain derived), and SNP AND (bdnf or brain derived). In a second step, the key word “bdnf” was also combined with mood, schizophrenia, anxiety, eating, and

Results

A total of 78 articles on studies of BDNF and psychiatric disorders conducted in 14 countries and published by May 17, 2006, were identified from applying our search strategies. On selection, 43 did not meet one or more of the inclusion criteria (see Supplement 1 for detailed information) and 35 met the inclusion criteria and were studied in this meta-analysis (Table 1). Some of these articles contributed more than one study to the meta-analysis (de Krom et al 2005, Jiang et al 2005,

Discussion

This meta-analysis includes data from 39 case-control studies and 5 psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders (subdivided into major depression disorders and bipolar disorders), and schizophrenia.

Large differences in the allelic frequencies for the BDNF Val66Met polymorphism between populations of different ethnic origins have previously been reported with similar results (Shimizu et al. 2004) and also coincide with the frequencies found in public

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Cited by (364)

Moderate associations between BDNF Val66Met gene polymorphism, musical expertise, and mismatch negativity
2023, Heliyon
Auditory predictive processing relies on a complex interaction between environmental, neurophysiological, and genetic factors. In this view, the mismatch negativity (MMN) and intensive training on a musical instrument for several years have been used for studying environment-driven neural adaptations in audition. In addition, brain-derived neurotrophic factor (BDNF) has been shown crucial for both the neurogenesis and the later adaptation of the auditory system. The functional single-nucleotide polymorphism (SNP) Val66Met (rs6265) in the BDNF gene can affect BDNF protein levels, which are involved in neurobiological and neurophysiological processes such as neurogenesis and neuronal plasticity. In this study, we hypothesised that genetic variation within the BDNF gene would be associated with different levels of neuroplasticity of the auditory cortex in 74 musically trained participants. To achieve this goal, musicians and non-musicians were recruited and divided in Val/Val and Met- (Val/Met and Met/Met) carriers and their brain activity was measured with magnetoencephalography (MEG) while they listened to a regular auditory sequence eliciting different types of prediction errors. MMN responses indexing those prediction errors were overall enhanced in Val/Val carriers who underwent intensive musical training, compared to Met-carriers and non-musicians with either genotype. Although this study calls for replications with larger samples, our results provide a first glimpse of the possible role of gene-regulated neurotrophic factors in the neural adaptations of automatic predictive processing in the auditory domain after long-term training.
Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis
2022, Neurologia
Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case–control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia.
This meta-analysis gathered data from 25 case–control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the “Leave one out” method, and we used the Egger test and Begg's funnel plot to identify publication bias.
Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value > .05.
Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case–control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.
Se sabe que los polimorfismos del gen BDNF provocan alteraciones neuronales y parecen ser un factor causal en muchos trastornos neuropsiquiátricos. Es por ello que se han llevado a cabo varios metaanálisis y estudios de casos y controles con el objetivo de evaluar la posible relación entre BDNF y la esquizofrenia.
Realizamos un metaanálisis de 25 estudios de casos y controles, que incluyó un total de 8.384 pacientes con esquizofrenia y 8.821 controles. Se analizó la relación entre el polimorfismo de nucleótido simple rs6265 y la esquizofrenia mediante odds ratios combinados y sus intervalos de confianza del 95% con 5 modelos genéticos diferentes. Utilizamos el método de validación cruzada dejando uno fuera («leave one out»), la prueba de Egger y el gráfico en embudo de Begg para identificar posibles sesgos de publicación.
Los estudios sobre el polimorfismo rs6265 (G/A) muestran una asociación no significativa con la esquizofrenia en los 5 modelos genéticos. En el análisis por subgrupos, no se encontró relación con las poblaciones caucásica y asiática (p > 0,05).
La presencia de polimorfismos rs6265 no aumenta la predisposición a desarrollar esquizofrenia. Sin embargo, se deben realizar más estudios de casos y controles sobre polimorfismos de BDNF, con muestras más numerosas y con individuos de diferentes grupos étnicos, para comprender mejor los mecanismos patogénicos de la enfermedad.
BDNF Val66Met polymorphism is associated with negative symptoms in early-onset schizophrenia spectrum and other psychotic disorders
2022, European Journal of Psychiatry
To investigate the clinical characteristics of adolescents with early-onset full psychotic disorders either with Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) or DRD2/ANKK1 Taq1A (rs1800497) polymorphisms.
101 cases with early-onset schizophrenia (EOS) or other psychotic spectrum disorders (SSD) and 150 healthy controls were included in the current study. Using the Positive and Negative Symptom Scale (PANSS), patient subgroups were compared for their psychotic symptoms, age-onset, duration of untreated illness, and family history of psychiatric disorders. The real-time polymerase chain reaction (RT-PCR) was implemented for genotyping procedures.
Study groups and patient subgroups were similar regarding their sociodemographic characteristics (16.4 ± 2.6 years, 62.2% male for all participants). Results did not reveal any difference between patients and healthy controls for DRD2/ANKK1 Taq1A and BDNF Val66Met genotypes. Patients with A1A2 (Gly/Lys) allele reported higher rates of substance use compared to A2A2 (Glu/Glu) counterparts. Other clinical variables were found similar. EOS/SSD group with Val66Met heterozygote allele revealed lower levels of negative symptoms than Val/Val homozygotes. Conversely, the age onset of full psychotic disorder, total positive symptom score, and total general psychopathology score of PANSS were found comparable between Val/Met and Val/Val groups. In the logistic regression model, Glu/Lys genotypes remained significant for the presence of substance use.
The interaction between substance use and the DRD2 gene should be investigated for the development of early-onset psychotic disorders. BDNF Val66Met polymorphism also could be a disease-modifying factor for the presence of negative symptoms.
Association between brain-derived neurotropic factor gene variant (rs6265; C > T) and schizophrenia, its psychopathology and intelligence
2021, European Journal of Psychiatry
The etiology of schizophrenia (SCZ) is not yet known, but the genetic factor has an essential role. Its heritability is estimated up to 85 percent. This study aimed to determine whether the selected brain-derived neurotropic factor (BDNF) gene variant (rs6265) is associated with SCZ, its psychopathology and intelligence quotient (IQ).
Rs6265 was genotyped in 159 participants, including 71 unrelated patients with SCZ (males = 40 [56%]) and 88 healthy controls (males = 35 [40%]). Psychopathology assessment was done by using positive and negative symptoms scale (PANSS), and IQ was measured by Wechsler adult intelligence scale (WAIS). COCAPHASE and CLUMP22 softwares were used to compare allele and genotype frequencies respectively. Two-way multivariate ANOVA was done using SPSS22 to evaluate the effects of the group (patients and healthy control) and the genotype on the test scores, including PANSS and WAIS scores, considering sex and smoking status as covariates.
The study showed that the BDNF rs6265 C allele and CC genotypes, psychopathology, including PANSS scores, and also IQ were significantly different in all, male and female patients compared to healthy participants. For rs6265, we found significantly higher frequencies of the C allele (P = 0.04) in all participants with SCZ.
The findings also revealed that BDNF polymorphism (rs6265) increased significantly the risk of SCZ in different genetic models.
The results showed that the BDNF rs6265 may be associated with the risk of SCZ development in an Iranian group of patients with SCZ. These results may be helpful in better understanding the role of the BDNF gene in the pathogenesis of the disorder.
Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation
2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.
BDNF-related mutations in major depressive disorder: A systematic review
2022, Acta Neuropsychiatrica

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Original ArticleBrain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia

Background

Methods

Results

Conclusions

Section snippets

Search Strategy

Results

Discussion

Neuron

Med Hypotheses

Neurosci Lett

Brain Res Mol Brain Res

Mol Genet Metab

Cell

Am J Hum Genet

Neurosci Lett

Prog Neuropsychopharmacol Biol Psychiatry

Psychiatry Res

Brain Res Mol Brain Res

J Subst Abuse

Biol Psychiatry

Neurobiol Aging

Life Sci

Neurosci Lett

Am J Hum Genet

Eur Neuropsychopharmacol

Biol Psychiatry

FEBS Lett

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Schizophr Res

Neurosci Lett

Schizophr Res

Neurosci Lett

Am J Hum Genet

Schizophr Res

Guilt by association

Nat Genet

Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision: DSM-IV-TR

BDNF in schizophrenia, depression and corresponding animal models

Mol Psychiatry

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

J Neural Transm

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

An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: Experience in Singapore

Drug Metab Rev

Regulation of neuropeptides in adult rat forebrain by the neurotrophins BDNF and NGF

Eur J Neurosci

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

Psychiatr Genet

A molecular and cellular theory of depression

Arch Gen Psychiatry

Bias in meta-analysis detected by a simple, graphical test

BMJ

Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: A family based association study

Am J Med Genet B Neuropsychiatr Genet

Mutation screen of the brain derived neurotrophic factor gene (BDNF): Identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder

Am J Med Genet B Neuropsychiatr Genet

Modulation of brain reward circuitry by leptin

Science

Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype

Am J Psychiatry

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

Neuroreport

Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: Case-control study of over 3000 individuals from the UK

Br J Psychiatry

Discovering endophenotypes for major depression

Neuropsychopharmacology

Endorphins, Eating Disorders and Other Addictive Behaviors

Once and again–Issues surrounding replication in genetic association studies

J Clin Endocrinol Metab

Co-morbidity of eating disorders and substance abuse review of the literature

Int J Eat Disord

Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior

Neuropsychobiology

Original Article
Brain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia