Rybakowski JK. BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. Pharmacogenomics 9: 1589-1593

Department of Adult Psychiatry, Poznan University of Medical Science, Szpitalna 27/33, 60-572 Poznan, Poland.
Pharmacogenomics (Impact Factor: 3.22). 12/2008; 9(11):1589-93. DOI: 10.2217/14622416.9.11.1589
Source: PubMed


The brain-derived neurotrophic factor (BDNF) gene has become a candidate gene for molecular-genetic studies of mood disorders and schizophrenia, and also for pharmacogenomics of drugs used in the treatment of these conditions, such as mood-stabilizers in bipolar mood disorder, antidepressants in depression, and antipsychotics in schizophrenia. It has been demonstrated that the functional Val66Met polymorphism of the gene can be associated with a number of clinical and pharmacological phenomena in these illnesses.

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    • ", 2002 ; Chen et al . , 2006 ; Rybakowski , 2008 ; Verhagen et al . , 2010 ) . "
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    ABSTRACT: Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF val66met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7 years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32 weeks gestation) were followed from birth to age 7 years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7 years using real time PCR. Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0·006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r= - 0.60; p=0.001) and poorer visual-motor integration (r= - 0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive performance in children born very preterm. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; DOI:10.1016/j.neuroscience.2015.08.044 · 3.36 Impact Factor
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    • "Approximately 30% of the Caucasian population are carriers of the methionine allele, with 4% being homozygous methionine (Met)/Met, with a substantially higher frequency of the methionine allele in Asian samples (Petryshen et al., 2010). The methionine allele leads to a reduction in the activity-dependent release of BDNF (Chen et al., 2005, 2006; Egan et al., 2003) and is associated with hippocampal-dependent memory function (Hariri et al., 2003) as well as with a variety of neuropsychiatric disorder (Duman & Monteggia, 2006; Groves, 2007; Rybakowski, 2008). The BDNF Val66Met polymorphism is also associated with direct measures of plasticity , such as structural plasticity in the cortex during learning and memory (Kleim et al., 2006; McHughen et al., 2010; Wang et al., 2014). "
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    ABSTRACT: Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
    Development and Psychopathology 02/2015; 27(1):137-50. DOI:10.1017/S0954579414001357 · 4.89 Impact Factor
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    • "A single nucleotide polymorphism (SNP) in the BDNF gene (that is, Val66Met; rs6265) has been shown to influence the activity of the BDNF protein. This SNP results in the substitution of valine (Val) to methionine (Met) [53]. Although the BDNF gene consists of several polymorphisms many are in high linkage disequilibrium and highly correlated [54,55]. "
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    ABSTRACT: Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051). The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.
    BMC Medicine 01/2014; 12(1):7. DOI:10.1186/1741-7015-12-7 · 7.25 Impact Factor
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