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DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF) Gene as a Potent Diagnostic Biomarker in Major Depression
Open accessAbstract
Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.
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![Figure 2 Hierarchic cluster analysis of subjects and their methylation profiles at CpG I of the BDNF gene. Two-way hierarchic cluster analysis of 38 samples (rows) and DNA methylation of CpG units at CpG I of the BDNF gene (columns). DNA methylation values are depicted by a pseudocolor scale as indicated (methylation increases from red [nonmethylated] to white [methylated]). Samples with overall poor data quality were removed before clustering. Gray denotes data of poor quality. Samples are color-coded according to the diagnoses of samples (legend depicted lower left). The stars(★) ahead of several CpG units indicate CpG units which have statistically significant p-values in subsequent analyses by t-test.](/paper-figures/fe4025408ac1437fa56ef69691a7b959/dna-methylation-profiles-of-the-brain-derived-neurotrophic-factor-bdnf-gene-as-a-figure-2.jpg)
![Figure 3 Hierarchic cluster analysis of subjects and their methylation profiles at CpG IV of the BDNF gene. Two-way hierarchic cluster analysis of 38 samples (rows) and DNA methylation of CpG units at CpG IV of the BDNF gene (columns). DNA methylation values are depicted by a pseudocolor scale as indicated (methylation increases from red [nonmethylated] to white [methylated]). Samples with overall poor data quality were removed before clustering. Gray denotes data of poor quality. Samples are color-coded according to the diagnoses of samples (legend depicted lower left).](/paper-figures/ac5f85d18e1d4efcb7c546bb5594e404/dna-methylation-profiles-of-the-brain-derived-neurotrophic-factor-bdnf-gene-as-a-figure-3.jpg)
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In the citing paper
“In depression, studies report low peripheral BDNF levels and higher promoter methylation, while antidepressants and electroconvulsive therapy (ECT) increase BDNF expression and reverse methylation”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [63]
Experimental — accuracy not yet measuredIn the citing paper
“and altered patterns of BDNF DNA methylation has been found in patients with cognitive impairments [ 167 , 169 , 170 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [169]
In the citing paper
“The DNA methylation profile of two CpG islands in the BDNF (BDNF-I and -IV) promoter and exon I was significantly different between depressed patients and healthy controls.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [127]
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Cites
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DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation
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Babenko, O., Kovalchuk, I., & Metz, G. A. S. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.11.013 · Cited by 513
DNA methylation of BDNF as a biomarker of early-life adversity
Kundakovic, M., Gudsnuk, K., Herbstman, J. B., Tang, D., Perera, F. P., & Champagne, F. A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408355111 · Cited by 426
Neural basis of major depressive disorder: Beyond monoamine hypothesis
Boku, S., Nakagawa, S., Toda, H., & Hishimoto, A. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12604 · Cited by 402
Smith, A. K., Kilaru, V., Klengel, T., Mercer, K. B., Bradley, B., Conneely, K. N., Ressler, K. J., & Binder, E. B. (2015) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32278 · Cited by 355
Brain-derived neurotrophic factor in mood disorders and antidepressant treatments
Castrén, E., & Kojima, M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.07.010 · Cited by 337
Metadata
- Authors
- Fuchikami, M., Morinobu, S., Segawa, M., Okamoto, Y., Yamawaki, S., Ozaki, N., Inoue, T., Kusumi, I., Koyama, T., Tsuchiyama, K., & Terao, T.
- Affiliations
- Hiroshima University (JP)
- Nagoya University (JP)
- Hokkaido University (JP)
- Oita University (JP)
- Corresponding author
- Morinobu, Shigeru
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-30
- Volume
- 6
- Issue
- 8
- Pages
- e23881
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3166055
- OpenAlex
- W2074918990
- Cited by
- 378
- References
- 35
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 15 · 2023: 10 · 2022: 21 · 2021: 57 · 2020: 24 · 2019: 29 · 2018: 27 · 2017: 34 · 2016: 34 · 2015: 32 · 2014: 38 · 2013: 24 · 2012: 18
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (acceptedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Hiroshima University Institutional Repository (submittedVersion, other-oa)
- Hiroshima University Acedemic Information Repository (Hiroshima University) (submittedVersion, cc-by)
- Funders
- Japan Society for the Promotion of Science (21591478)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- major depressive disorder, DNA methylation, brain-derived neurotrophic factor, BDNF gene, epigenetic biomarkers, diagnostic biomarkers, CpG islands, promoter methylation, peripheral blood DNA, depression diagnosis
- MeSH terms
- Adult, Major Depressive Disorder, Depressive Disorder, Major, Exons, Female, Humans, Male, Middle Aged, Promoter Regions, Genetic, Biomarkers, Case-Control Studies, CpG Islands, DNA Methylation, Brain-Derived Neurotrophic Factor, Epigenesis, Genetic
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