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Cited by 378Epigenetics and DNA MethylationTreatment of Major DepressionGenetic Associations and Epidemiology

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DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF) Gene as a Potent Diagnostic Biomarker in Major Depression

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Fuchikami, Manabu, Morinobu, Shigeru, Segawa, Masahiro, Okamoto, Yasumasa, Yamawaki, Shigeto, Ozaki, Norio, Inoue, Takeshi, Kusumi, Ichiro, Koyama, Tsukasa, Tsuchiyama, Kounosuke, Terao, Takeshi·2011·PLoS ONE
DOI 10.1371/journal.pone.0023881PMC PMC3166055
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Abstract

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 1 The schema of CpGs and primers used for DNA methylation analyses. The target region used for methylation analysis consists of 1092 bp including 81 CpGs upstream of exon I, and 1137 bp including 28 CpGs upstream of exon IV.
Figure 1 The schema of CpGs and primers used for DNA methylation analyses. The target region used for methylation analysis consists of 1092 bp including 81 CpGs upstream of exon I, and 1137 bp including 28 CpGs upstream of exon IV.CC BY · PubMed Central
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.
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.CC BY · PubMed Central
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).
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).CC BY · PubMed Central

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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)
DOI
10.1371/journal.pone.0023881
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
Licence
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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