DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients

Ikegame, Tempei; Bundo, Miki; Sunaga, Fumiko; Asai, Tatsuro; Nishimura, Fumichika; Yoshikawa, Akane; Kawamura, Yoshiya; Hibino, Hiroki; Tochigi, Mamoru; Kakiuchi, Chihiro; Sasaki, Tsukasa; Kato, Takeshi; Kasai, Kiyoto; Iwamoto, Kazuya

doi:10.1016/j.neures.2013.08.004

Cited by 116 publications

(102 citation statements)

References 39 publications

(45 reference statements)

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“…Although DNA methylation shows significant between-tissue variation, some interindividual differences in DNA methylation are correlated across brain and blood of healthy subjects (33), suggesting that epigenetic profiling of peripheral tissue may be useful for studies of brain disorders. Consistent with this hypothesis, DNA methylation changes have been found both in psychiatric postmortem brain samples (34,35) and in peripheral blood of the living psychiatric patients (12)(13)(14). However, a challenge to this field of study is whether epigenetic markers in peripheral tissues can predict functionally relevant epigenetic changes in the brain and consequent behavioral and psychiatric outcomes.…”

Section: Discussionmentioning

confidence: 81%

“…However, despite this between-species discordance, it is striking that BDNF DNA methylation differences in humans that may serve as a predictor of behavioral vulnerability could be detected as early as at birth. In addition to promoter IV (34,43), other BDNF gene regions such as promoters I (13,14) and VI (10) can also be sensitive to epigenetic effects of early-life adversity and may confer psychiatric risk. Therefore, although our study provides a proof of principle that BDNF DNA methylation in the blood may predict behavioral vulnerability, future more comprehensive epigenetic analyses of the BDNF gene in response to other early-life exposures and in psychiatric patients are warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggested that concentrations of BDNF protein in the blood (serum or plasma) may represent peripheral manifestation of depression (48) and schizophrenia (49) and could be used as a biomarker for therapeutic efficacy (50). Similarly, BDNF DNA methylation changes have been found in the peripheral blood of patients suffering from depression (13), bipolar disorder (12), schizophrenia (14), and eating disorders (51), and a change in BDNF DNA methylation status correlated with a positive response to psychotherapy in borderline personality disorder (52). In addition, within a psychiatric population, high BDNF DNA methylation was strongly associated with the history of child maltreatment (51,52).…”

Section: Discussionmentioning

confidence: 99%

“…Several ubiquitous environmental exposures known to affect brain development (e.g., prenatal stress, famine, pollution/toxins) have been associated with epigenetic variation in human peripheral tissues (7)(8)(9)(10)(11). In addition, there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients (12)(13)(14). However, because epigenetic marks are by definition tissue-and cell type-specific, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain and related phenotypic changes.…”

mentioning

confidence: 99%

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DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

357

244

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Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.epigenetics | biomarker | BDNF | bisphenol A | early life

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

357

244

View full text Add to dashboard Cite

show abstract

“…In rodent models of early-life stress, increased methylation of BDNF promoter IV was found to be associated with decreased mRNA expression of BDNF in the prefrontal cortex (Ivy et al, 2008;Roth et al, 2009). In addition to early-life adversity, BDNF methylation patterns appear to be sex-dependent (Ikegame et al, 2013). A recent study comparing BDNF promoter I and IV methylation levels between 100 controls and 100 schizophrenic patients reported a gender-dependant DNA methylation status in peripheral blood (Ikegame et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Stenz

Zewdie

Laforge-Escarra

et al. 2015

Neuroscience Research

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a b s t r a c tSeveral 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.

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DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain

Smith

Kilaru

Klengel

et al. 2014

American J of Med Genetics Pt B

303

273

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DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. DNA methylation (HumanMethylation450 BeadChip) was assessed in saliva and blood samples from 64 adult African Americans. Analyses were conducted using linear regression adjusted for appropriate covariates, including estimated cellular proportions. DNA methylation from brain tissues (cerebellum, frontal cortex, entorhinal cortex, and superior temporal gyrus) was obtained from a publically available dataset. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e., CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Finally, DNA methylation in saliva appeared more similar to patterns from each of the brain regions examined overall than methylation in blood. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits.

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DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients

Cited by 116 publications

References 39 publications

DNA methylation of BDNF as a biomarker of early-life adversity

DNA methylation of BDNF as a biomarker of early-life adversity

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

DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain

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