DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation
Open accessAbstract
Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n = 20), MDD patients with (n = 14) or without serious suicidal ideation (n = 10), we studied methylation of the stress-associated genes, Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1). In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.
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Altered FKBP5 methylation is associated with both depression severity and SSRI responsiveness.
“altered FKBP5 methylation is associated with both depression severity and SSRI responsiveness (Roy et al., 2017)”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Roy et al., 2017
The Results section, “Correlation of DNA methylation with MADRS” (page unavailable), reports no significant association between FKBP5 methylation and depression severity in any MDD group. The Methods section, “Subjects” (page unavailable), says participants were psychotropic-drug-free before sampling; the paper does not report SSRI responsiveness. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredMethylation patterns of stress-related genes, including NR3C1 and FKBP5, in peripheral blood mononuclear cells are associated with both depression severity and antidepressant responsiveness.
“Accumulating evidence indicates that methylation patterns of stress-related genes, including NR3C1 and FKBP5, in peripheral blood mononuclear cells are associated with both depression severity and antidepressant responsiveness (Roy et al., 2017).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Roy et al., 2017
The Results section, “Correlation of DNA methylation with MADRS” (page unavailable), reports a significant association with depression severity for NR3C1 only in patients with serious suicidal ideation; FKBP5 was not significantly associated with severity in any group. The Methods section, “Subjects” (page unavailable), says participants were free of psychotropic drugs before sampling, and the passages do not report antidepressant responsiveness. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn PBMCs, NR3C1 hypermethylation with reduced expression and FKBP5 hypomethylation with increased expression correlate with depression severity and suicidal ideation.
“In PBMCs, NR3C1 hypermethylation with reduced expression and FKBP5 hypomethylation with increased expression correlate with depression severity and suicidal ideation (Roy et al., 2017)”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Roy et al., 2017
The Discussion reports NR3C1 promoter hypermethylation and reduced expression in PBMCs of MDD patients with suicidal ideation. But the Abstract and Discussion report FKBP5 hypermethylation with reduced expression—the opposite of the claimed FKBP5 pattern. The paper discusses depression and suicidal ideation, but the cited passages do not establish a correlation with depression severity; its secondary analysis also found no significant difference between MDD patients with and without serious suicidal ideation. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPeripheral blood mononuclear cells (PBMCs) and other circulating molecules can partially reflect central epigenetic states.
“Evidence indicates that peripheral blood mononuclear cells (PBMCs) and other circulating molecules can partially reflect central epigenetic states, supporting patient stratification, severity assessment, treatment prediction, and personalized care (Milic et al., 2025; Roy et al., 2017).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Roy et al., 2017
The Results (MeDIP analysis; page not provided) show altered DNA methylation in PBMCs from patients with MDD, supporting the peripheral-epigenetic-measurement part of the claim. The paper does not establish that PBMCs reflect central epigenetic states, examine other circulating molecules, or demonstrate the stated clinical applications. (LLM, conf=0.82)
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- Authors
- Roy, B., Shelton, R. C., & Dwivedi, Y.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Dwivedi, Yogesh
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 89
- Pages
- 115-124
- ISSN
- 0022-3956 (ISSN-L)
- PMC
- PMC5391149
- OpenAlex
- W2588311118
- Cited by
- 139
- References
- 74
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 11 · 2023: 10 · 2022: 14 · 2021: 19 · 2020: 18 · 2019: 12 · 2018: 26 · 2017: 7 · 2015: 1
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Alabama at Birmingham
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Institute of Mental Health (R21MH081099, R01MH101890, R01MH082802, R01MH100616, R01MH107183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Keywords
- DNA methylation, major depressive disorder, suicidal ideation, stress-related genes, promoter hypermethylation, brain-derived neurotrophic factor, NR3C1, FKBP5, CRHBP, CRHR1, hypothalamic-pituitary-adrenal axis, epigenetic regulation, gene expression, peripheral blood mononuclear cells
- MeSH terms
- CRF Receptor, Type 1, Tacrolimus Binding Protein 5, Adult, Major Depressive Disorder, Female, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Promoter Regions, Genetic, Psychiatric Status Rating Scales, Receptors, Glucocorticoid, RNA, Messenger, Statistics as Topic, Stress, Psychological, Receptors, Corticotropin-Releasing Hormone, DNA Methylation, Brain-Derived Neurotrophic Factor, Tacrolimus Binding Proteins, Epigenesis, Genetic, Immunoprecipitation, Suicidal Ideation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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