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Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms

Department of Psychiatry, Course of Integrated Brain Sciences, Medical Informatics, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-8-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Neuroscience Letters (Impact Factor: 2.06). 07/2006; 401(1-2):1-5. DOI: 10.1016/j.neulet.2006.02.054
Source: PubMed

ABSTRACT Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that promotes several functions of neurons and modulates neurotransmissions. It has been reported that there are alterations of BDNF levels in schizophrenic brains and that BDNF gene expressional changes would be responsible for the etiology of schizophrenia. Recent studies have shown that a variation of BDNF gene (Val66Met polymorphism) affects the function of neurons, and is associated with several neurological and psychiatrical disorders. We investigated the relationship between BDNF Val66Met polymorphism and the onset age as well as levels of clinical symptoms in 159 of chronic schizophrenia in-patients diagnosed by DSM-IV. The mean onset ages were 27.5+/-9.5 for BDNF Val/Val, 25.5+/-7.4 for BDNF Val/Met and 22.9+/-6.0 for BDNF Met/Met and this polymorphism was significantly associated with age at onset (P=0.023). The mean Brief Psychiatric Rating Scale scores (BPRS) were significantly different among those three groups (P=0.003). No significant differences were demonstrated comparing the BDNF genotype distributions of positive and negative family history (P=0.21). Our investigation indicates that the BDNF gene Val66Met polymorphism is related to the onset age of schizophrenia and the levels of clinical symptoms that remain after long-term antipsychotic treatment.

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    • "Others have shown an association between the BDNF gene single nucleotide polymorphism (SNP) val66met and schizophrenia in some populations (Neves- Pereira et al., 2005; Gratacos et al., 2007). Although this has not been replicated in other population and genome-wide association studies, other groups have shown associations in patients with schizophrenia between the SNP and age of onset (Numata et al., 2006; Chao et al., 2008; Zhou et al., 2010), cognitive performance (Ho et al., 2006; Rybakowski et al., 2006; Kebir et al., 2009; Lu et al., 2012), and neuroimaging measures (Szeszko et al., 2005; Koolschijn et al., 2010; Smith et al., 2012). Interestingly, there are major sex-differences in the age of onset of schizophrenia and also symptom severity, with males showing earlier onset of disease and greater cognitive deficits (Hafner et al., 1993; Goldstein et al., 1998). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET) has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the disorder.
    Frontiers in Cellular Neuroscience 06/2013; 7:92. DOI:10.3389/fncel.2013.00092 · 4.18 Impact Factor
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    • "Several genetic studies have shown a significant association between the BDNF Val66Met polymorphism and several psychiatric disorders.35-37) In patient with schizophrenia, the BDNF Val66Met polymorphism was found to be associated with age at onset.38) The Val66Met genotype may be involved in the expression of psychiatric phenotype in psychiatric disorders by modulating the activity of many neurotransmitter systems.4,39,40) "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays an important role in cell survival, differentiation, and cell death as well as in neural plasticity. Recent studies have suggested that BDNF is involved in the pathogenesis of bipolar disorder. The aim of this study was to investigate the association of the genetic variations of the BDNF gene with bipolar disorder in Korea. We also studied the possible association of these genetic variants with clinical features. The allelic and genotypic distributions of Val66Met polymorphism of the BDNF gene were analyzed using a polymerase chain reaction-based method in 184 bipolar patients and 214 controls. Analysis was performed to investigate an association of the Val66Met polymorphism of the BDNF gene and the clinical features in bipolar patients. No significant difference was found between bipolar patients and controls in the genotype and allele frequencies for the investigated BDNF polymorphism. However, the age of onset of bipolar disorder among the Val/Val (25.57), Val/Met (30.42) and Met/Met (32.45) genotype groups were significantly different (p=0.037). This study suggests that Val66Met polymorphisms are unlikely to contribution to the genetic predisposition to bipolar disorder as a whole. But Val66Met polymorphism may be associated with age of onset of the disorder, further studies designed to investigate the relationship in a larger population may be warranted.
    Clinical Psychopharmacology and Neuroscience 12/2012; 10(3):163-7. DOI:10.9758/cpn.2012.10.3.163
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    • "A Val to Met substitution at codon 66 (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, results in less efficient intracellular trafficking and decreased activity-dependent BDNF secretion [140]. The Met66 allele has been reported to be associated with the age of onset [141] in patients with schizophrenia and a BDNF-sex-cannabis interaction has been shown [142]. Cannabis use predicted an earlier age of onset in male patients independently of genotype, whereas in female patients, cannabis use was only associated with age of onset in BDNF Metcarriers . "
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    ABSTRACT: Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model.
    Current pharmaceutical design 06/2012; 18(32):5024-35. DOI:10.2174/138161212802884609 · 3.29 Impact Factor
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