Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians

Recent studies have demonstrated a role of the brain-derived neurotrophic factor (BDNF) in schizophrenia. An association between the Val66Met BDNF polymorphism has been reported but the results of different studies are inconsistent. An aim of the present article is to study the allele and genotype distribution in patients with schizophrenia (783) and mentally healthy controls (633). No statistically significant between-group differences have been found. When the group of patients has been stratified by sex and form of schizophrenia, the higher frequency of the Val/Val genotype is observed in the subgroup of men with continuous (chronic) schizophrenia as compared to men with attack-like form (p = 0.047). Clinical symptoms assessed with the PANSS were more severe in male patients with the Val/Val genotype. The Val66Met polymorphism was not associated with forms of schizophrenia or clinical symptoms in female patients. The results obtained suggest that the association between the BDNF gene and schizophrenia may be related to sex and clinical heterogeneity of disease. The Val/Val genotype is associated with severer form of schizophrenia in men.     

Modulating effect of Val66Met polymorphism of brain-derived neurotrophic factor gene on clinical and psychological characteristics of patients with schizophrenia

The brain-derived neurotrophic factor (BDNF) gene is an important candidate gene for schizophrenia. The association of BDNF with schizophrenia has been extensively analyzed using the polymorphism Val66Met. There is accumulating evidence that Val66Met is associated with clinical presentations of schizophrenia rather than with the disease itself. In this study, BDNF allele and genotype distributions were compared in patients (n = 1785) and healthy controls (n = 1092). There was no association between the Val66Met polymorphism and schizophrenia. The marker was not associated with the presence of the affective syndrome either. At the same time, the ValVal genotype was associated with higher anxiety levels in male patients as assessed with PANSS. Patients’ personality traits were characterized using the personality inventories EPI, MMPI, and STAI (n = 363), and their cognitive functions, attention (n = 282) and verbal fluency (n = 392), were evaluated. Patients with the ValVal genotype showed higher levels of anxiety (by MMPI) and better performance on neurocognitive tests. The genotype and trait anxiety (by STAI score) had an interaction effect on cognitive functions. In patients with higher anxiety, performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety, the ValVal genotype was associated with significantly better performance. This effect should be taken into account when studying associations of the Val66Met polymorphism with cognitive functions in patients with schizophrenia.     

Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM.     

Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression

There is a strong etiological link between brain‐derived neurotrophic factor and depression, but the neurocellular mechanisms and gene–environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain‐derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11–17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the ‘differential‐susceptibility’ hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events.     

Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls

Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype?×?diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level?×?genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism.     

BDNF Val66Met Polymorphism Is Associated with Self-Reported Empathy

Empathy is an important driver of human social behaviors and presents genetic roots that have been studied in neuroimaging using the intermediate phenotype approach. Notably, the Val66Met polymorphism of the Brain-derived neurotrophic factor (BDNF) gene has been identified as a potential target in neuroimaging studies based on its influence on emotion perception and social cognition, but its impact on self-reported empathy has never been documented. Using a neurogenetic approach, we investigated the association between the BDNF Val66Met polymorphism and self-reported empathy (Davis’ Interpersonal Reactivity Index; IRI) in a sample of 110 young adults. Our results indicate that the BDNF genotype is significantly associated with the linear combination of the four facets of the IRI, one of the most widely used self-reported empathy questionnaire. Crucially, the effect of BDNF Val66Met goes beyond the variance explained by two polymorphisms of the oxytocin transporter gene previously associated with empathy and its neural underpinnings (OXTR rs53576 and rs2254298). These results represent the first evidence suggesting a link between the BDNF gene and self-reported empathy and warrant further studies of this polymorphism due to its potential clinical significance.     

Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor.     

BDNF Val66Met 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.     

Association Study of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor Gene with Clozapine-Induced Metabolic Syndrome: Preliminary Results

The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program''s Adult Treatment Panel III. We genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR = 2.39; 95% CI: 1.05–5.41; p = 0.039; corrected p = 0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p = 0.005; corrected p = 0.03), but not in females (p = 0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p = 0.007; corrected p = 0.042 and p = 0.002; corrected p = 0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings.     

BDNF Val66Met Variant and Smoking in a Chinese Population

Several recent studies have supported the hypothesis that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, might be associated with nicotine addiction. Association studies have also suggested that the BDNF gene might play a role in the susceptibility to nicotine dependence but results appear contradictory. The present work was therefore undertaken to examine the association of smoking with the BDNF Val66Met gene polymorphism in Chinese population. The BDNF Val66Met gene polymorphism was examined in 628 healthy male volunteers including 322 smokers and 306 non-smokers. Also, the BDNF serum levels were measured in 136 smokers and 97 nonsmokers. Our results showed no significant association between the BDNF Val66Met polymorphism or serum levels among smokers and non-smokers. Smokers with the Met allele however started smoking significantly earlier than those with the Val/Val genotype (mean age at smoking initiation of 17.4, 17.9 and 21.2 years for Met/Met, Met/Val, and Val/Val, respectively; both p<0.05). No other significant differences between other variables such as number of cigarettes per day, smoking severity as measured by the Fagerstrom Test for Nicotine Dependence (FTND) score and carbon monoxide (CO) levels (all p>0.05). In addition, there was no main effect of genotype on serum BDNF levels. Our findings suggest that the BDNF Val66Met polymorphism may not be involved in susceptibility to smoking among the Chinese male population, but may influence the age at which smoking is initiated. However, the findings must be interpreted with caution because of the relatively small sample size for an association study. Results should be confirmed in a larger cohort.     

Exploring the Impact of BDNF Val66Met Genotype on Serotonin Transporter and Serotonin-1A Receptor Binding

Background

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) may impact on the in-vivo binding of important serotonergic structures such as the serotonin transporter (5-HTT) and the serotonin-1A (5-HT_1A) receptor. Previous positron emission tomography (PET) studies on the association between Val66Met and 5-HTT and 5-HT_1A binding potential (BP_ND) have demonstrated equivocal results.

Methods

We conducted an imaging genetics study investigating the effect of Val66Met genotype on 5-HTT or 5-HT_1A BP_ND in 92 subjects. Forty-one subjects (25 healthy subjects and 16 depressive patients) underwent genotyping for Val66Met and PET imaging with the 5-HTT specific radioligand [¹¹C]DASB. Additionally, in 51 healthy subjects Val66Met genotypes and 5-HT_1A binding with the radioligand [carbonyl-¹¹C]WAY-100635 were ascertained. Voxel-wise and region of interest-based analyses of variance were used to examine the influence of Val66Met on 5-HTT and 5-HT_1A BP_ND.

Results

No significant differences of 5-HTT nor 5-HT_1A BP_ND between BDNF Val66Met genotype groups (val/val vs. met-carrier) were detected. There was no interaction between depression and Val66Met genotype status.

Conclusion

In line with previous data, our work confirms an absent effect of BDNF Val66Met on two major serotonergic structures. These results could suggest that altered protein expression associated with genetic variants, might be compensated in vivo by several levels of unknown feedback mechanisms. In conclusion, Val66Met genotype status is not associated with changes of in-vivo binding of 5-HTT and 5-HT_1A receptors in human subjects.     

Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.     

Gender,Brain-Derived Neurotrophic Factor Val66Met,and Frequency of Methamphetamine Use

BackgroundFrequency of pretreatment methamphetamine (MA) use is an important predictor of outcomes of treatment for MA dependence. Preclinical studies suggest females self-administer more MA than males, but few clinical studies have examined potential sex differences in the frequency of MA use. Estrogen increases expression of brain-derived neurotrophic factor (BDNF), which has effects on MA-induced striatal dopamine release and protects against MA-induced neurotoxicity.ObjectiveWe examined potential effects of sex, the Val66Met polymorphism in BDNF, and their interaction on frequency of MA use among 60 Caucasian MA-dependent volunteers screening for a clinical trial.MethodsData was taken from 60 Caucasian MA-dependent volunteers screening for a clinical trial.ResultsFemales reported significantly more pretreatment days with MA use in the past 30 days than males. There was a significant interaction between sex and BDNF Val66Met, with the highest frequency of MA use among females with Val/Val genotype.ConclusionsThese results, although preliminary, add to the literature documenting sexual dimorphism in response to stimulants, including MA, and suggest a potential biological mechanism involving BDNF that might contribute to these differences. Additional research characterizing the biological basis of altered response to MA among females is warranted.     

Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population

Recent data suggest that brain‐derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM‐IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD‐I) or type II (BPD‐II) and 386 matched health controls were enrolled, and TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ² = 6.18, df = 2, P = 0.046; allele: χ² = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64–0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD‐I and BPD‐II separately. For BPD‐I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = ?2.27, df = 144, P = 0.025); for BPD‐II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD‐II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD‐I and BPD‐II.     

Genetic variation on the BDNF gene is not associated with differences in white matter tracts in healthy humans measured by tract‐based spatial statistics

The brain‐derived neurotrophic factor (BDNF) is a member of the neurotrophin family and involved in nerve growth and survival. It has also become a major research focus in the investigation of both cognitive and affective processes in the human brain in the last years. Especially, a single nucleotide polymorphism on the BDNF gene called BDNF Val66Met gained a lot of attention, because of its effect on activity‐dependent BDNF secretion and its link to negative emotionality and impaired memory processes. A well‐replicated finding from genetic structural imaging showed that carriers of the less frequent 66Met allele show diminished gray matter volume in several areas of the temporal lobe. New imaging techniques like diffusion tensor imaging now allow investigating the influence of BDNF Val66Met on white matter integrity. We applied tract‐based spatial statistics in a brain image dataset including n = 99 healthy participants. No significant differences between the 66Met and homozygous 66Val carriers were observed when correcting for multiple comparisons. In summary, the BDNF Val66Met polymorphism seems not to play a substantial role with respect to the modulation of the white matter integrity in healthy subjects. Although not in the focus of this study, we also investigated the influence of Eysenck's Personality Questionnaire on the white matter tracts. No significant results could be observed.     

Identification of BDNF Sensitive Electrophysiological Markers of Synaptic Activity and Their Structural Correlates in Healthy Subjects Using a Genetic Approach Utilizing the Functional BDNF Val66Met Polymorphism

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.     

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val⁶⁶Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.     

Recapitulation of the association of the Val66Met polymorphism of BDNF gene with BMI in Koreans

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) regulates food intake and the control of body weight. A common polymorphism in human BDNF, Val66Met (single-nucleotide polymorphism database (dbSNP) no. rs6265), impairs intracellular trafficking, resulting in the reduced secretion of BDNF. Several European studies have indicated that Val66Met is associated with BMI. In this study, we examined the association of the Val66Met polymorphism with BMI in Koreans (n = 20,270) from three independent epidemiological cohorts. All three studies observed a consistent association of this polymorphism with BMI, and their combined analysis demonstrated a robust correlation (β = -0.17 ± 0.03 and P = 5.6 × 10(-8)). We also examined the effect of smoking on the link between Val66Met and BMI. The association of Val66Met with BMI was statistically significant only in the smoking group, reflecting a possible interaction between smoking and the BDNF polymorphism for BMI. Thus, we have confirmed BDNF as a genetic risk factor for BMI in an Asian population and hypothesize that the Val66Met mutation influences individual differences in BMI. In addition, smoking might interact with BDNF Val66Met to modulate BMI.