Brain-derived Neurotrophic Factor Promoter Methylation Research Articles

Brain-derived neurotrophic factor (BDNF) variants and promoter I methylation are associated with prolonged nocturnal awakenings in older adults.

Brain-derived neurotrophic factor (BDNF) is important for sleep physiology. This study investigates whether BDNF variants and promoter I methylation may be implicated in sleep disturbances in older adults. Genotyping was performed for seven BDNF single nucleotide polymorphisms (SNPs) in 355 community-dwelling older adults (aged ≥65 years) and BDNF exon 1 promoter methylation was measured in blood samples at baseline (n=153). Self-reported daytime sleepiness and insomnia, ambulatory polysomnography measures of sleep continuity and architecture, and psychotropic drug intake were assayed during follow-up. Logistic regression adjusted for age, sex, comorbidities, body mass index, and psychotropic drug intake. Associations were found specifically between wake time after sleep onset (WASO) and four SNPs in the participants not taking psychotropic drugs, whereas in those taking drugs, the associations were either not significant (rs6265 and rs7103411) or in the reverse direction (rs11030101 and rs28722151). Higher BDNF methylation levels were found at most CpG units in those with long WASO and this varied according to psychotropic drug use. The reference group with short WASO not taking drugs showed the lowest methylation levels and the group with long WASO taking treatment, the highest levels. Some SNPs also modified the associations, the participants carrying the low-risk genotype having the lower methylation levels. This genetic and epigenetic study demonstrated blood BDNF promoter methylation to be a potential biomarker of prolonged nocturnal awakenings in older people. Our results suggest the modifying effect of psychotropic drugs and BDNF genetic variants in the associations between methylation and WASO.

Long-term ambient air pollution exposure and DNA methylation of peripheral brain-derived neurotrophic factor promoter.

This study aimed to investigate the association between air pollutants and methylation of peripheral brain-derived neurotrophic factor (BDNF) promoters. A total of 101 individuals were recruited in this panel study. BDNF promoter methylation was detected by bisulfite-PCR amplification and pyrosequencing. Participants' exposure to air pollutants was estimated using a satellite-based random forests approach. A generalized estimated equation model with natural cubic splines was employed to examine the associations between air pollutants and BDNF promoter methylation levels. The associations between air pollution and BDNF promoter methylation showed nonlinear curves with threshold effects. The threshold concentration for the association of nitrogen dioxide (NO2) with average methylation level was 59.7μg/m3, and that for the association of particulate matter ≤1µm in diameter (PM1) with CpG2 methylation level was 70.9μg/m3. The percent change of average methylation level at the 95th percentile of NO2 against the threshold concentration was 43.25% (95%CI: 13.10%, 73.40%), and that of CpG2 methylation at the 95th percentile of PM1 was 128.29% (95%CI: 43.27%, 213.31%). Overall, long-term exposures of PM1, PM2.5, PM10, and NO2 were associated with significant changes in BDNF promoter methylation levels with threshold effects.

Dysregulated Methylation Patterns in Exon IV of the Brain-Derived Neurotrophic Factor (BDNF) Gene in Nicotine Dependence and Changes in BDNF Plasma Levels During Smoking Cessation.

IntroductionSeveral studies reported dysregulated protein levels of brain-derived neurotrophic factor (BDNF) in smokers and during cessation. However, the epigenetic regulation of the BDNF gene has not yet been investigated. We measured the plasma levels of BDNF and the epigenetic regulation of exon IV of the BDNF gene in smokers compared to healthy controls over a cessation period of 14 days.MethodWe measured BDNF plasma levels and BDNF promoter methylation in 49 smokers and 51 non-smokers at baseline, day 7, and day 14 of smoking cessation. Mean methylation levels of 11 Cytosine Guanosine dinucleotides of exon IV of the BDNF gene were determined via bisulfite sequencing.ResultsBDNF plasma and methylation levels were significantly lower in healthy controls when compared with smokers across all time points. BDNF levels for smokers decreased significantly during the cessation period. Comparing the sexes, female smokers showed significantly lower plasma BDNF levels than healthy controls at baseline and over 14 days of cessation. Male and female smokers showed significantly higher mean methylation rates than non-smokers at baseline. In male smokers, mean methylation levels decreased significantly during the cessation period.ConclusionOur findings replicate the findings of previous studies that BDNF plasma levels are altered in smokers. Furthermore, BDNF expression and gene methylation are altered during the first 14 days of cessation. Our novel findings of dysregulated methylation patterns in exon IV of the BDNF gene further support the thesis that BDNF plays a role in nicotine dependence.

Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington's Disease Patients.

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the complex BDNF promoter have been associated with its deregulation in pathological conditions. BDNF has gained increased attention as a potential biomarker of disease; but currently, the conflicting results from measurements of BDNF in different biofluids difficult the assessment of its utility as a biomarker for HD. Here, we measured BDNF protein levels in plasma (n = 85) and saliva (n = 81) samples from premanifest and manifest HD patients and normal controls using ELISA assays. We further examined DNA methylation levels of BDNF promoter IV using DNA derived from whole blood of HD patients and healthy controls (n = 40) using pyrosequencing. BDNF protein levels were not significantly different in plasma samples across diagnostic groups. Plasma BDNF was significantly correlated with age in control subjects but not in HD patients, nor were significant gender effects observed. Similar to plasma, salivary BDNF was correlated with age only in control subjects, with no gender effects observed. Importantly, we detected significantly lower levels of salivary BDNF in premanifest and manifest HD patients compared to control subjects, with lower BDNF levels being observed in premanifest patients within a predicted 10 years to disease onset. Salivary and plasma BDNF levels were not significantly correlated with one another, suggesting different origins. DNA methylation at four out of the 12 CpG sites studied in promoter IV were significantly altered in HD patients in comparison to controls. Interestingly, methylation at three of these CpG sites was inversely correlated to the Hospital Anxiety and Depression Scale (HADS) scores. BDNF promoter methylation was not correlated with motor or cognitive scores in HD patients, and was not associated with sex or age in neither disease nor control groups. Conclusion: Our studies show that BDNF protein levels are decreased in saliva; and BDNF promoter methylation increased in blood in HD subjects when compared to controls. These findings suggest that salivary BDNF measures may represent an early marker of disease onset and DNA methylation at the BDNF promoter IV, could represent a biomarker of psychiatric symptoms in HD patients.

Is Peripheral BDNF Promoter Methylation a Preclinical Biomarker of Dementia?

Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n = 769) and buccal samples during follow-up (n = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ4. Multivariable logistic regression analyses determined the association between BDNF methylation and both prevalent and incident dementia. Adjustment for gender, age, education, APOEɛ4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ-0.5%, 95% CI:-0.9,-0.04, p = 0.03, p = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p = 0.02, p = 0.14 adjusted and Δ-1.5%, OR:0.85, SE:0.06, p = 0.03, p = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r=-0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing.

BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response.

Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 ± 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] ≥ 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (≥ 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT00974155

Brain-derived neurotrophic factor promoter methylation and cortical thickness in recurrent major depressive disorder.

Recent studies have reported that methylation of the brain-derived neurotrophic factor (BDNF) gene promoter is associated with major depressive disorder (MDD). This study aimed to investigate the association between cortical thickness and methylation of BDNF promoters as well as serum BDNF levels in MDD. The participants consisted of 65 patients with recurrent MDD and 65 age- and gender-matched healthy controls. Methylation of BDNF promoters and cortical thickness were compared between the groups. The right medial orbitofrontal, right lingual, right lateral occipital, left lateral orbitofrontal, left pars triangularis, and left lingual cortices were thinner in patients with MDD than in healthy controls. Among the MDD group, right pericalcarine, right medical orbitofrontal, right rostral middle frontal, right postcentral, right inferior temporal, right cuneus, right precuneus, left frontal pole, left superior frontal, left superior temporal, left rostral middle frontal and left lingual cortices had inverse correlations with methylation of BDNF promoters. Higher levels of BDNF promoter methylation may be closely associated with the reduced cortical thickness among patients with MDD. Serum BDNF levels were significantly lower in MDD, and showed an inverse relationship with BDNF methylation only in healthy controls. Particularly the prefrontal and occipital cortices seem to indicate key regions in which BDNF methylation has a significant effect on structure.

Associations of BDNF promoter methylation with the morbidity and suicidal ideation in patients with first-episode major depressive disorder

Objective To explore the role of brain derived neurotrophic factor(BDNF) promoter methylation for the morbidity of depression patients, and to investigate the relevance between BDNF promoter methylation and the suicidal ideation in patients with first-episode major depressive disorder. Methods The peripheral blood samples from 23 cases of depression patients with suicide ideation, 24 cases of depression patients without suicide ideation, and 27 healthy controls were grouped using simple randomization method, and the methylation status of CpG island of BDNF promoter were subsequently evaluated using bisulphite sequencing. Results The methylation rates(median, quartile interval) of depression patients with suicidal ideation, depression patients without suicidal attempt, and the healthy control were detected as follows, CPG-1: 2.60 (0.28), 2.70 (0.60), 6.40 (1.00); CPG-2: 3.35 (1.15), 3.20 (1.00), 14.50 (2.60); CPG-3: 1.50 (0.40), 1.50 (0.60), 4.60 (0.90); CPG-4: 1.75 (0.90), 1.50 (0.50), 3.90 (0.90); CPG-5: 0.80 (0.58), 0.90 (1.00), 5.70 (2.10); CPG-6: 6.05 (1.03), 6.20 (1.70), 14.50 (1.70); CPG-7: 10.55 (1.68), 10.10 (1.50), 14.70 (1.70); CPG-8: 16.35 (0.90), 16.40(1.00), 4.80 (1.20); CPG-9: 4.20 (4.80), 4.70 (1.30), 28.50 (19.30); CPG-10: 10.25 (1.08), 10.30 (1.20), 4.30 (0.90); CPG-11: 62.80 (4.05), 62.30 (4.00), 37.20 (2.60); CPG-12: 5.60 (1.05), 5.60 (1.30), 12.30 (1.80); CPG-13: 4.15 (1.10), 4.10 (1.10), 59.70 (4.90); CPG-14: 5.45 (0.78), 5.70 (0.90), 6.30 (0.60); CPG-15: 3.70 (0.70), 3.90 (1.00), 62.40 (6.50); CPG-16: 8.05 (1.75), 8.10 (1.60), 74.30 (50.90); CPG-17: 3.20 (0.78), 3.20 (0.80), 32.40 (13.20); CPG-18: 1.90 (0.48), 1.80 (0.40), 2.30 (0.30); CPG-19: 35.00 (6.27), 35.20 (3.00), 64.20 (44.70). There was an obvious difference in methylation rate among three groups, which was statistically significant (P<0.01). However, no statistical significance for the methylation rates was observed between the depression patients with suicidal ideation and without suicidal ideation. Interestingly, statistical significance for the methylation rates were observed when compared the depression patients with suicidal ideation with healthy control (P<0.05), and the depression patients without suicidal ideation with healthy control (P<0.05). Conclusion The results show that the association is observed between BDNF promoter methylation and the morbidity of depressive disorder, but not between BDNF promoter methylation and the suicidal ideation of depression patients. Key words: Brain derived neurotrophic factor; Methylation; Depression; Suicide

Do changes in the BDNF promoter methylation indicate the risk of alcohol relapse?

The neurotrophic growth factor brain derived neurotrophic factor (BDNF) was linked to the risk of alcohol relapse in clinical studies.In this study we investigated alterations in the methylation of the BDNF gene during alcohol withdrawal (day 1, 7 and 14) in 99 male alcohol-dependent patients compared to age matched healthy males (n=33). In particular, we aimed to investigate a possible association between the BDNF promoter methylation and the self-reported duration of alcohol abstinence before relapse.Mean methylation of the BDNF promoter was significantly increased in alcohol-dependent patients compared to the healthy controls (F=10.014, p<0.001) and decreased significantly during alcohol-withdrawal (F=10.014, p<0.001). Moreover, mean methylation was associated with depressive (F=2.014, p<0.001) and anxious symptoms in the alcohol-dependent patients (F=2.228, p<0.001). On day 14 of alcohol-withdrawal we found significantly higher methylation rates in those patients who abstained longer before relapse compared to those patients who abstained shorter (F=9.938, p<0.001).Our results suggest an association between BDNF expression and the symptomatology of alcohol withdrawal and imply that changes in the methylation of the BDNF IV gene may contribute to alcohol consumption.

BDNF promoter methylation and genetic variation in late-life depression.

The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age⩾65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean=0.4%, P=0.0002; promoter IV, Δ mean=5.4%, P=0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.

Population difference in the association of BDNF promoter methylation with mild cognitive impairment in the Xinjiang Uygur and Han populations

BackgroundMild cognitive impairment (MCI) is a clinical transitional stage between normal aging and Alzheimer disease, which leads to memory loss and a reduction in cognitive function. Brain derived neurotrophic factor (BDNF) plays an important role in neuronal development and plasticity. The aim of this study was to explore the association between BDNF promoter methylation and MCI in the Xinjiang Uygur and Han populations. MethodsA DNA methylation assay using bisulfite pyrosequencing technology was performed on 96 Uygur and 96 Han Chinese individuals from Xinjiang province, China. ResultsWe found a significantly higher BDNF methylation level in Han MCI cases than in Uygur MCI cases in males from Xinjiang province (p=0.022). In addition, the methylation level was significantly higher in Xinjiang Han healthy Chinese individuals (Northwestern China) than in Ningbo Han healthy Chinese individuals (Southeastern China) (Female and Male: p=1.17E−05; Female: p=0.020; Male: p=1.37E−04). But our results showed no significant association of BDNF methylation with MCI in either the Uygur or Han Chinese populations (p>0.05). Further gender-based subgroup analyses did not find any significant results (p>0.05). ConclusionOur results indicate that different levels of BDNF methylation may be present in different populations and environments. This study also provides further information regarding the relationship between BDNF methylation levels and MCI in Xinjiang Uygur and Han ethnic groups.

Promoter Methylation and BDNF and DAT1 Gene Expression Profiles in Patients with Drug Addiction

Background: Drug addiction is a brain disorder that has negative consequences for individuals and society. Addictions are chronic relapsing diseases of the brain that are caused by direct drug-induced effects and persevering neuroadaptations at the epigenetic, neuropeptide and neurotransmitter levels. Because the dopaminergic system has a significant role in drug abuse, the purpose of this study was to analyze the methylation and expression profile of brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in individuals with drug addiction. Materials and Methods:BDNF and DAT1 promoter methylation were investigated with a methylation-specific polymerase chain reaction (PCR) technique in blood samples from 75 individuals with drug addiction and 65 healthy controls. The expression levels of BDNF and DAT1 were assessed in 12 mRNA samples from the blood of patients and compared to the samples of healthy controls (n = 12) with real-time quantitative reverse transcription PCR. Results: No significant differences were found in the methylation of BDNF and DAT1 between patients and controls, but the relative levels of expression of BDNF and DAT1 mRNA differed significantly in the patients compared to controls (p < 0.0001). Conclusion: These results showed that the methylation status of the BDNF and DAT1 genes had no significant function in the processes of drug addiction.

Longitudinal associations between BDNF promoter methylation and late-life depression

Reduced brain-derived neurotrophic factor (BDNF) function has been suggested as a risk factor for late-life depression. BDNF secretion is influenced by epigenetic (DNA promoter methylation) and genetic (val66met polymorphism) profiles. We investigated the independent and interactive effects of BDNF methylation and val66met polymorphism on late-life depression. In total, 732 Korean community residents aged ≥65 years were evaluated, and 521 of them without depression at baseline were followed up 2 years later. Depression was determined using the Geriatric Mental State Schedule, and depression severity was evaluated with the Geriatric Depression Scale. Demographic and clinical covariates were obtained. The effects of BDNF methylation and polymorphism on the diagnosis of depression were investigated using a multivariate logistic regression model, and the relationships between BDNF methylation and depression severity were evaluated using partial correlation tests. Higher BDNF methylation was independently associated with the prevalence and incidence of depression and severe depressive symptoms. No significant methylation-genotype interactions were found. BDNF promoter methylation could be a proxy biomarker for depression late in life.

BDNF promoter methylation associated with suicidal ideation in patients with breast cancer.

Brain-derived neurotrophic factor (BDNF) has been considered a risk factor for suicidality. BDNF secretion is influenced by epigenetic (DNA methylation) and genetic (val66met polymorphism) profiles. We aimed to investigate the independent effects of BDNF promoter methylation status on suicidal ideation as well as the effects of its interaction with the val66met polymorphism in patients with breast cancer. A total of279 patients with breast cancer were evaluated 1 week after breast surgery, and 244 (87%) were followed up 1 year later. Suicidal ideation was identified using the item addressing suicidal thoughts on the Beck Depression Inventory. The independent effects of BDNF methylation status on suicidal ideation at two points was investigated using multivariable logistic regression models. The two-way interactive effects of BDNF methylation status and the val66met polymorphism on suicidal ideation were also estimated using the same models. Increased BDNF methylation was significantly associated with suicidal ideation and depression 1 year after breast surgery, and this association was independent of potential covariates, including previous depression, current depressive symptoms, and BDNF genotype. No significant methylation-genotype interactions were found. The BDNF hypothesis and the epigenetic origin of suicidality in patients with breast cancer were supported. BDNF gene methylation status may be a biological marker for suicidality in patients with breast cancer.

BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy.

We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial.

Elevation of peripheral BDNF promoter methylation links to the risk of Alzheimer's disease.

Brain derived neurotrophic factor (BDNF) has been known to play an important role in various mental disorders or diseases such as Alzheimer's disease (AD). The aim of our study was to assess whether BDNF promoter methylation in peripheral blood was able to predict the risk of AD. A total of 44 AD patients and 62 age- and gender-matched controls were recruited in the current case-control study. Using the bisulphite pyrosequencing technology, we evaluated four CpG sites in the promoter of the BDNF. Our results showed that BDNF methylation was significantly higher in AD cases than in the controls (CpG1: p = 10.021; CpG2: p = 0.002; CpG3: p = 0.007; CpG4: p = 0.005; average methylation: p = 0.004). In addition, BDNF promoter methylation was shown to be significantly correlated with the levels of alkaline phosphatase (ALP), glucose, Lp(a), ApoE and ApoA in males (ALP: r = −0.308, p = 0.042; glucose: r = −0.383, p = 0.010; Lp(a): r = 0.333, p = 0.027; ApoE: r = −0.345, p = 0.032;), ApoA levels in females (r = 0.362, p = 0.033), and C Reactive Protein (CRP) levels in both genders (males: r = −0.373, p = 0.016; females: r = −0.399, p = 0.021). Our work suggested that peripheral BDNF promoter methylation might be a diagnostic marker of AD risk, although its underlying function remains to be elaborated in the future.

BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues

Several psychiatric disorders have been associated with CpG methylation changes in CG rich promoters of the brain-derived neurotrophic factor (BDNF) mainly by extracting DNA from peripheral blood cells. Whether changes in peripheral DNA methylation can be used as a proxy for brain-specific alterations remains an open question. In this study we aimed to compare DNA methylation levels in BDNF promoter regions in human blood cells, muscle and brain regions using bisulfite-pyrosequencing. We found a significant correlation between the levels of BDNF promoter I methylation measured in quadriceps and vPFC tissues extracted from the same individuals (n=98, Pearson, r=0.48, p=4.5×10−7). In the hippocampus, BDNF promoter I and IV methylation levels were strongly correlated (Pearson, n=37, r=0.74, p=1.4×10−7). We found evidence for sex-dependent effect on BDNF promoter methylation levels in the various tissues and blood samples. Taken together, these data indicate a strong intra-individual correlation between peripheral and brain tissue. They also suggest that sex determines methylation patterns in BDNF promoter region across different types of tissue, including muscle, brain, and blood.

P.2.b.004 Longitudinal associations between BDNF promoter methylation and late-life depression

Introduction: Late-life depression is associated with an elevated risk of suicide as well as functional and cognitive impairments, which confer a risk of dementia [1]. Considering these negative consequences of geriatric depression, understanding the etiology of depression is an important step toward early detection and effective treatment of depression in the elderly population. Reduced brain-derived neurotrophic factor (BDNF) function has been suggested as a risk factor for late-life depression. BDNF secretion is influenced by epigenetic (DNA promoter methylation) [2] and genetic (val66met polymorphism) profiles [3]. We investigated the independent and interactive effects of BDNF methylation and val66met polymorphism on late-life depression. Methods: In total, 732 Korean community residents aged 65 years were evaluated, and 521 of them without depression at baseline were followed up 2 years later. The prevalence and incidence of depression were determined using the Geriatric Mental State Schedule, and depression severity was evaluated with the Geriatric Depression Scale. Covariates included age, sex, education, chronic physical disorders, cognitive function, and disability. The effects of BDNF methylation and polymorphism on the diagnosis of depression were investigated using a multivariate logistic regression model, and the relationships between BDNF methylation and depression severity were evaluated using partial correlation tests. Results: Of the 631 participants without depression at baseline, 521 (82.6%) were followed up. Depression was identified 2 years later in 86 (16.5%) of the 521 participants who were followed up. After applying Bonferroni correction, the prevalence of depression at baseline was significantly associated with higher BDNF promoter methylation at CpG site 9 and a higher average methylation percentage. Furthermore, the incidence of depression at the 2-year follow up was significantly associated with higher BDNF promoter methylation at CpG site 9 and a higher average methylation percentage. The results of multivariate logistic regression analysis after adjustment for covariates were that the prevalence and incidence of depression were independently associated with a higher methylation percentage at CpG site 9 and a higher average methylation percentage after applying Bonferroni correction. Partial correlations of BDNF methylation percentages with the GDS scores were summarized as follows. After applying Bonferroni correction, higher baseline GDS scores were significantly correlated with a higher methylation percentage at CpG site 9 and higher average methylation percentage after adjustment for sex, number of chronic medical illnesses, cognitive function, and disability. Additionally, higher GDS scores at follow-up were significantly correlated with a higher average methylation percentage in the same adjusted model. However, there were no significant associations between BDNF promoter methylation percentages and genotype. Furthermore, there were no significant interactive effects of BDNF methylation percentages and genotype on the prevalence or incidence of depression in the multivariate logistic regression model. Conclusions: Higher BDNF methylation was independently associated with prevalence and incidence of depression as well as severe depressive symptoms. No significant methylation-genotype interactions were found. BDNF promoter methylation could be a proxy biomarker for depression late in life.

Association of BDNF promoter methylation and genotype with suicidal ideation in elderly Koreans.

Brain-derived neurotrophic factor (BDNF) has been considered a risk factor for suicidal behavior in adult populations. BDNF secretion is influenced by epigenetic (DNA promoter methylation) and genetic (val66met polymorphism) profiles. We investigated the independent and interactive effects of BDNF methylation status and val66met polymorphisms on late-life suicidal ideation. In total, 732 Korean community residents aged 65+ years were evaluated; of 639 without suicidal ideation, 579 (90.6%) were followed up 2 years later. The prevalence and incidence of suicidal ideation were ascertained using the Geriatric Mental State Schedule. Sociodemographic and clinical covariates included age, sex, education, depressive symptoms, cognitive function, and disability. The independent effects of BDNF methylation status on the prevalence and incidence of suicidal ideation were investigated using multivariate logistic regression models. The two-way interactions of BDNF methylation status and val66met polymorphism on suicidal ideation were assessed using the same models. Higher BDNF methylation status was significantly associated with both prevalence and incidence of suicidal ideation, independent of potential covariates. No significant methylation-genotype interaction was found. The BDNF hypothesis and the epigenetic origin of the suicidal behavior were supported, even in old age. BDNF promoter methylation status may be useful as a biological marker for suicidality in late life.

Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder.

BackgroundBipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD.MethodsFifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG ‘units’ across three amplicons of BDNF promoters 3 and 5.Results and DiscussionMethylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values ≤ 0.004) with medium to large effect sizes (Cohen's d ≥ 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 ×10−5) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD.Electronic supplementary materialThe online version of this article (doi:10.1186/2194-7511-1-28) contains supplementary material, which is available to authorized users.