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.
"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). "
[Show abstract][Hide abstract] 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
"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) . Although the BDNF gene consists of several polymorphisms many are in high linkage disequilibrium and highly correlated [54,55]. "
[Show abstract][Hide abstract] 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
"The Val66Met polymorphism, which results in a substitution from valine to methionine at codon 66 in the human BDNF gene, is associated with disrupted intracellular trafficking and release of BDNF (Chen et al., 2004). Several studies have shown an association of this polymorphism with aspects of schizophrenia (Rybakowski, 2008; Buckley et al., 2011). For example, homozygous carriers (Met/Met) show an increased risk of schizophrenia relative to the heterozygous state (Gratacos et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a severe psychiatric disorder with a complex and variable set of symptoms. Both genetic and environmental mechanisms are involved in the development of the illness and lead to structural and neurochemical abnormalities in the brain. An intriguing facet of schizophrenia is sex differences, which have been described for nearly all features of the illness, including the peak age of onset, symptoms and treatment response. The ovarian hormone, estrogen, may be protective against schizophrenia and evidence is accumulating that estrogen may exert this effect via an interaction with brain-derived neurotrophic factor (BDNF). Both estrogen and BDNF have trophic effects on the developing brain and promote synaptic plasticity and maintain neurons well into adulthood. Major neurotransmitter systems including dopaminergic, serotonergic and glutamatergic pathways are modulated and supported by estrogen and BDNF. Despite their commonalities, estrogen and BDNF have mostly been examined independently but increasing evidence suggests an interaction between the two in brain regions pertinent to schizophrenia. This review will focus on the role of estrogen and BDNF in clinical and animal studies of schizophrenia. We include animal models of neurotransmitter dysfunction and genetic manipulation to show how estrogen may provide a protective effect in schizophrenia, including through mediating BDNF expression and activity. This posited estrogen-BDNF interaction could play a key role in modulating sex-dependent results reported in animal work as well as sex differences in clinical aspects of schizophrenia.
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