BDNF Val66Met Polymorphism Research Articles

The BDNFval66met polymorphism and individual differences in temperament in 4-month-old infants: A pilot study

Individual differences in infants’ temperament are under genetic control. We investigated the association between brain-derived-neurotrophic-factor (BDNFval66met) polymorphism and temperament in 63 full-term infants. Met-carriers (N=25) had lower Regulatory capacities compared to val-homozygotes (N=38). These findings suggest that the BDNF polymorphism affects early temperament individual differences.

Influence of the BDNF Val66Met polymorphism on the balance of excitatory and inhibitory neurotransmission and relationship to plasticity in human cortex

Influence of the BDNF Val66Met polymorphism on the balance of excitatory and inhibitory neurotransmission and relationship to plasticity in human cortex

BDNF Val66Met polymorphism modulates brain activity responses following rTMS-induced memory dysfunction

BDNF Val66Met polymorphism modulates brain activity responses following rTMS-induced memory dysfunction

Cannabis use, COMT, BDNF and age at first-episode psychosis

Although an interaction between COMT Val158Met and BDNF Val66Met polymorphisms with cannabis use has been proposed with respect to the risk of psychosis emergence, findings remain inconclusive. The aim of the present study was to evaluate the different possible associations between these polymorphisms and early cannabis use and the age at the first episode of psychosis. The relationship between age at psychosis onset and COMT Val158Met and BDNF Val66Met polymorphisms with early cannabis use as well as those factors associated with early cannabis use were investigated. Among 260 Caucasian first-episode psychosis patients, early cannabis use and the presence of the met-allele from the BDNF Val66Met polymorphism were significantly associated with age at psychosis onset. Furthermore, early cannabis use was significantly associated with male gender in the logistic regression analysis. These findings provide evidence of the important role of early cannabis use and the Val66Met BDNF polymorphism on age at psychosis onset and they point out to sex-specific differences in cannabis use patterns.

BDNFVal66Met polymorphism moderates the link between child maltreatment and reappraisal ability

Child maltreatment is associated with increased risk for virtually all common mental disorders, but it is not yet clear why. One possible mechanism is emotion regulation ability. The present study investigated for the first time the influence of a BDNF Val66Met genotype × child maltreatment interaction on emotion regulation, and compared differential susceptibility and diathesis-stress models. A sample of N = 254 healthy volunteers were genotyped for the BDNF Val66Met polymorphism and underwent an experimental assessment of reappraisal ability (i.e. the success of using reappraisal to downregulate negative affect). A self-report instrument previously validated against a clinical interview was used to investigate child maltreatment. There was a significant BDNF Val66Met genotype × child maltreatment interaction (B = -0.31, P < 0.015), with Met carriers showing both the lowest level of reappraisal ability in maltreated participants, and the highest level of reappraisal ability in non-maltreated participants. By assessing alternative models, we found that the best fitting model was in line with strong differential susceptibility. As expected, reappraisal ability was negatively correlated with depressive symptoms. Therefore, the BDNF Val66Met polymorphism moderates the link between child maltreatment and emotion regulation ability. Future studies could investigate whether improving reappraisal in maltreated BDNF Met carriers results in reduced risk for mental disorders.

T25 - The VAL66MET Bdnf Genetic Polymorphism Does Not Modify The Association Between Major Depression And Body Mass Index (BMI)

Background Depression and obesity are highly prevalent diseases in the general population, responsible of disability burden worldwide. Recently, a bidirectional relationship between both disorders has been described but the biological explanation of this reciprocal link is still unknown. The association between the BDNF Val66Met polymorphism and depression has been described in several studies. Besides, this polymorphism has also been associated with eating behavior, eating disorders and body mass index (BMI). The aim of this study is to investigate the genetic influence of the BDNF Val66Met polymorphism in relation to BMI in a population-based sample of individuals with major depression versus controls. Methods We performed a case-control study including 337 individuals with major depression and 921 healthy controls from the Granad∑p and PISMA-ep studies from the region of Andalusia (Spain). The MINI was used to establish the diagnostic of depression. Height and weight data reported from each individual was used to calculate BMI using the formula: weight(kg)/height(m)2. T-tests were used to analyze the association between major depression and BMI. Linear regression models for quantitative traits assuming an additive genetic model were applied to analyze the association between the BDNF Val66Met polymorphism and BMI. First, the analyses were carried out in the whole sample, and then separately in cases and controls. The regression analyses were adjusted by sex, age, province and depression status in the whole sample. When cases and controls were analyzed separately, sex, age and province were included as covariates in the models. Finally, we performed interaction analysis between the Val66Met polymorphism, major depression and BMI. The statistical analyses were carried out with the software PLINK v1.06. Results We found a statistically significant association between major depression and BMI. The individuals with depression had significantly higher BMI values compared to controls (cases: BMI=27.54 (SD=5.75); controls: BMI=26.75 (SD=4.76); t=-2.34, P=0.009). No significant differences were found in the allelic or genotypic frequencies distribution when cases and controls were compared. Linear regression analyses did not show a significant association between the Val66Met polymorphism and BMI, neither in the whole sample (β=-0.1035, p=0.651) nor when cases and controls were analyzed separately (cases: β=-0.791, p=0.134; controls: β=-0.177, p=0.470). No interaction between the Val66Met polymorphism and major depression was found in relation to BMI (β=-0.787, P=0.14). Discussion Our results show an association between BMI and major depression confirming the results from previous studies. However, our study does not support the implication of the BDNF Val66Met polymorphism in the genetic relationship between BMI and major depression.

Association between the BDNF Val66Met polymorphism and BMI in Mexican children

Association between the BDNF Val66Met polymorphism and BMI in Mexican children

Expression and methylation of BDNF in the human brain in schizophrenia

Objectives: To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene.Methods: DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing. Expression, methylation and genotype data were correlated and examined for association with schizophrenia.Results: There was 43% more of the BDNF V-VIII-IX transcript in schizophrenia samples. BDNF mRNA expression and DNA methylation of seven CpG sites were not associated with schizophrenia after accounting for age and PMI effects. BDNF mRNA expression and DNA methylation were not altered by Val66Met after accounting for age and PMI effects. DNA methylation of one CpG site had a marginally significant positive correlation with mRNA expression in schizophrenia subjects.Conclusions: Schizophrenia risk was not associated with differential BDNF mRNA expression and DNA methylation. A larger age-matched cohort with comprehensive clinical history is required to accurately identify the effects of genotype, mRNA expression and DNA methylation on schizophrenia risk.

Association of the BDNF Val66Met polymorphism with BMI in chronic schizophrenic patients and healthy controls.

Several lines of evidence suggest that a functional variant of the brain-derived neurotrophic factor gene (BDNF Val66Met) correlates with a number of eating disorders. Studies have also shown that the BDNF Val66Met polymorphism was associated with weight gain in patients with schizophrenia on long-term antipsychotic treatment. This study aimed to determine whether there was a relationship between the BDNF Val66Met polymorphism and BMI values in patients with chronic schizophrenia. We compared 308 Han Chinese patients with schizophrenia on long-term antipsychotic medication with 304 healthy normal controls on BDNF polymorphism. Body weight and BMI were measured before breakfast on the day blood samples were taken. The symptomatology of schizophrenia was assessed using the Positive and Negative Syndrome Scale. The results showed that the BDNF Val66Met polymorphism was associated with the BMI value, with genotype having a strong effect on the mean BMI value in male but not in female patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment.

Harsh Parenting and Serotonin Transporter and BDNF Val66Met Polymorphisms as Predictors of Adolescent Depressive Symptoms

Depressive symptoms are prevalent and rise during adolescence. The present study is a prospective investigation of environmental and genetic factors that contribute to the growth in depressive symptoms and the frequency of heightened symptoms during adolescence. Participants included 206 mother–father–adolescent triads (M age at Time 1 = 13.06 years, SD = .51, 52% female). Harsh parenting was observationally assessed during a family conflict paradigm. DNA was extracted from saliva samples and genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms. Adolescents provide self-reports of depressive symptoms annually across early adolescence. The results reveal Gene × Environment interactions as predictors of adolescent depressive symptom trajectories in the context of harsh parenting as an environmental risk factor. A BDNF Val66Met × Harsh Parenting interaction predicted the rise in depressive symptoms across a 3-year period, whereas a 5-HTTLPR × Harsh Parenting interaction predicted greater frequency in elevated depressive symptoms. The findings highlight the importance of unique genetic and environmental influences in the development and course of heightened depressive symptoms during adolescence.

Association of the brain-derived neurotrophic factor Val66Met polymorphism with negative symptoms severity, but not cognitive function, in first-episode schizophrenia spectrum disorders

ObjectiveA functional polymorphism of the brain-derived neurotrophic factor gene (BDNF) Val66Met has been associated with cognitive function and symptom severity in patients with schizophrenia. It has been suggested that the Val66Met polymorphism has a role as a modulator in a range of clinical features of the illness, including symptoms severity, therapeutic responsiveness, age of onset, brain morphology and cognitive function. However, little work has been done in first-episode schizophrenia (FES) spectrum disorders. The objective of this study is to investigate the association of the BDNF Val66Met polymorphism on cognitive function and clinical symptomatology in FES patients. MethodsUsing a cross-sectional design in a cohort of 204 patients with FES or a schizophrenia spectrum disorder and 204 healthy matched controls, we performed BDNF Val66Met genotyping and tested its relationship with cognitive testing (attention, working memory, learning/verbal memory and reasoning/problem-solving) and assessment of clinical symptom severity. ResultsThere was no significant influence of the BDNF allele frequency on cognitive factor scores in either patients or controls. An augmented severity of negative symptoms was found in FES patients that carried the Met allele. ConclusionsThe results of this study suggest that in patients with a first-episode of schizophrenia or a schizophrenia spectrum disorder, the BDNF Val66Met polymorphism does not exert an influence on cognitive functioning, but is associated with negative symptoms severity. BDNF may serve as suitable marker of negative symptomatology severity in FES patients within the schizophrenia spectrum.

Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia.

Previously, we determined that rodents' vulnerability to food restriction (FR)-evoked wheel running during adolescence (activity-based anorexia, ABA) is associated with failures to increase GABAergic innervation of hippocampal and medial prefrontal pyramidal neurons. Since brain-derived neurotrophic factor (BDNF) promotes GABAergic synaptogenesis, we hypothesized that individual differences in this vulnerability may arise from differences in the link between BDNF bioavailability and FR-evoked wheel running. We tested this hypothesis in male BDNF-Val66Met knock-in mice (BDNFMet/Met), known for reduction in the activity-dependent BDNF secretion and elevated anxiety-like behaviors. We found that 1) in the absence of FR or a wheel (i.e., control), BDNFMet/Met mice are more anxious than wild-type (WT) littermates, 2) electron microscopically verified GABAergic innervations of pyramidal neurons of BDNFMet/Met mice are reduced at distal dendrites in hippocampal CA1 and medial prefrontal cortex, 3) following ABA, WT mice exhibit anxiety equal to those of the BDNFMet/Met mice and have lost GABAergic innervation along distal dendrites, 4) BDNFMet/Met mice show blunted ABA vulnerability, and 5) unexpectedly, GABAergic innervation is higher at somata of BDNFMet/Met mice than of WT. We conclude that lamina-specific GABAergic inhibition is important for regulating anxiety, whether arising from environmental stress, such as food deprivation, or genetically, such as BDNFMet/Met single nucleotide polymorphism.

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

The modifying effect of the BDNF Val66Met polymorphism on the neurophysiological characteristics of verbal information processing

Human functional MRI studies frequently reveal the joint activation of parietal and of lateral and mesial frontal areas during various cognitive tasks. To analyze the geometrical organization of those networks, we used an automatized clustering algorithm that parcels out sets of areas based on their similar profile of task-related activations or deactivations. This algorithm allowed us to reanalyze published fMRI data (Simon, O., Mangin, J.F., Cohen, L., Le Bihan, D., Dehaene, S., 2002. Topographical layout of hand, eye, calculation, and language-related areas in the human parietal lobe. Neuron 33, 475–487) and to reproduce the previously observed geometrical organization of activations for saccades, attention, grasping, pointing, calculation, and language processing in the parietal lobe. Further, we show that this organization extends to lateral and mesial prefrontal regions. Relative to the parietal lobe, the prefrontal functional geometry is characterized by a partially symmetrical anteroposterior ordering of activations, a decreased representation of effector-specific tasks, and a greater emphasis on higher cognitive functions of attention, higher-order spatial representation, calculation, and language. Anatomically, our results in humans are closely homologous to the known connectivity of parietal and frontal regions in the macaque monkey.

Predicting Response Trajectories during Cognitive-Behavioural Therapy for Panic Disorder: No Association with the BDNF Gene or Childhood Maltreatment.

BackgroundAnxiety disorders are highly prevalent and result in low quality of life and a high social and economic cost. The efficacy of cognitive-behavioural therapy (CBT) for anxiety disorders is well established, but a substantial proportion of patients do not respond to this treatment. Understanding which genetic and environmental factors are responsible for this differential response to treatment is a key step towards “personalized medicine”. Based on previous research, our objective was to test whether the BDNF Val66Met polymorphism and/or childhood maltreatment are associated with response trajectories during exposure-based CBT for panic disorder (PD).MethodWe used Growth Mixture Modeling to identify latent classes of change (response trajectories) in patients with PD (N = 97) who underwent group manualized exposure-based CBT. We conducted logistic regression to investigate the effect on these trajectories of the BDNF Val66Met polymorphism and two different types of childhood maltreatment, abuse and neglect.ResultsWe identified two response trajectories (“high response” and “low response”), and found that they were not significantly associated with either the genetic (BDNF Val66Met polymorphism) or childhood trauma-related variables of interest, nor with an interaction between these variables.ConclusionsWe found no evidence to support an effect of the BDNF gene or childhood trauma-related variables on CBT outcome in PD. Future studies in this field may benefit from looking at other genotypes or using different (e.g. whole-genome) approaches.

Higher reward value of starvation imagery in anorexia nervosa and association with the Val66Met BDNF polymorphism.

Recent studies support the idea that abnormalities of the reward system contribute to onset and maintenance of anorexia nervosa (AN). Next to cues coding for overweight, other research suggest cues triggering the proposed starvation dependence to be pivotally involved in the AN pathogenesis. We assessed the characteristics of the cognitive, emotional and physiologic response toward disease-specific pictures of female body shapes, in adult AN patients compared with healthy control (HC) women. Frequency and amplitude of skin conductance response (SCR) in 71 patients with AN and 20 HC were registered during processing of stimuli of three weight categories (over-, under- and normal weight). We then assessed the role of the Val66Met BDNF polymorphism as a potential intermediate factor. AN patients reported more positive feelings during processing of underweight stimuli and more negative feelings for normal- and overweight stimuli. The SCR showed a group effect (P=0.007), AN patients showing overall higher frequency of the response. SCR within patients was more frequent during processing of underweight stimuli compared with normal- and overweight stimuli. The Met allele of the BDNF gene was not more frequent in patients compared with controls, but was associated to an increased frequency of SCR (P=0.008) in response to cues for starvation. A higher positive value of starvation, rather than more negative one of overweight, might more accurately define females with AN. The Met allele of the BDNF gene could partly mediate the higher reward value of starvation observed in AN.

BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke.

Persistent motor impairment is common but highly heterogeneous poststroke. Genetic polymorphisms, including those identified on the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness. To determine whether BDNF and APOE genotypes influence motor improvement facilitated by poststroke upper-limb rehabilitation. BDNF-Val66Met and APOE isoform genotypes were determined using leukocyte DNA for 55 community-dwelling patients 2-123 months poststroke. All patients completed a dose-matched upper-limb rehabilitation program of either Wii-based Movement Therapy or Constraint-induced Movement Therapy. Upper-limb motor function was assessed pre- and post-therapy using a suite of functional measures. Motor function improved for all patients post-therapy, with no difference between therapy groups. In the pooled data, there was no significant effect of BDNF or APOE genotype on motor function at baseline, or following the intervention. However, a significant interaction between the level of residual motor function and BDNF genotype was identified (p = 0.029), whereby post-therapy improvement was significantly less for Met allele carriers with moderate and high, but not low motor function. There was no significant association between APOE genotype and therapy outcomes. This study identified a novel interaction between the BDNF-Val66Met polymorphism, motor-function status, and the magnitude of improvement with rehabilitation in chronic stroke. This polymorphism does not preclude, but may reduce, the magnitude of motor improvement with therapy, particularly for patients with higher, but not lower residual motor function. BDNF genotype should be considered in the design and interpretation of clinical trials.

Editorial: Non-invasive Brain Stimulation and Plasticity Changes in Aging.

Editorial: Non-invasive Brain Stimulation and Plasticity Changes in Aging.

Partial replication of two rumination-related candidate gene studies

ABSTRACTTwo recent papers associated candidate genes with brooding rumination, a possible cognitive endophenotype for depression, in children ages 8–14 years. Stone et al. reported that BDNF val66met polymorphism predicted brooding in adolescence. Woody et al. reported that children carrying at least one copy of a CRHR1 TAT haplotype reported less brooding than their peers in the presence of maternal depression. We attempted to replicate and extend these findings in a sample of twins aged 12–16 years. We analyzed the BDNF val66met (rs6265) polymorphism and two (rs242924 and rs7209436) out of three single nucleotide polymorphisms (SNPs) that Woody et al. used to create a CRHR1 haplotype. We controlled for maternal history of depression and clustering within families. Unlike Stone et al., we found higher brooding among BDNF Met carriers. This main effect was qualified by an interaction with pubertal status, with the effect driven by more physically mature participants. Similar to Woody et al., we found an interaction between CRHR1 SNPs and maternal depression, with the homozygous minor genotype acting as a protective factor against brooding in the presence of maternal depression. Findings provide partial support for the influence of candidate genes in two environmentally sensitive systems on brooding.

No association between BDNF Val66Met polymorphism and treatment response in obsessive-compulsive disorder in the Japanese population.

AimBrain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, and it promotes the development and function of dopaminergic and serotonergic neurons. The Met allele of the BDNF Val66Met polymorphism is associated with a decrease in activity-dependent secretion of BDNF compared with the Val allele, and a number of studies have provided evidence for the association between this polymorphism and obsessive-compulsive disorder (OCD). The purpose of this study was to investigate whether this functional variant of the BDNF gene is associated with OCD and treatment response in patients with OCD in the Japanese population.MethodsWe first performed a case–control association study between the BDNF Val66Met polymorphism and OCD (175 cases and 2,027 controls). Then, we examined an association between this polymorphism and treatment response in 96 patients with OCD.ResultsWe found no significant association between the Met allele and OCD risk or between the Met allele and treatment responses to selective serotonin reuptake inhibitors or serotonin reuptake inhibitor with an atypical antipsychotic (P>0.05).ConclusionOur results suggest that the BDNF Val66Met polymorphism may not be associated as a risk factor for developing OCD or with therapeutic response in patients with OCD in the Japanese population.