BDNF genetic variants and methylation: effects on cognition in major depressive disorder
Open accessAbstract
Brain-derived neurotrophic factor (BDNF) gene regulation has been linked to the pathophysiology of major depressive disorder (MDD). MDD patients show cognitive deficits, and altered BDNF regulation has a relevant role in neurocognitive functions. Our goal was to explore the association between BDNF genetic and epigenetic variations with neurocognitive performance in a group of MDD patients and healthy controls considering possible modulating factors. The sample included 134 subjects, 64 MDD patients, and 70 healthy controls. Clinical data, childhood maltreatment, and neurocognitive performance were assessed in all participants. Eleven single nucleotide polymorphisms (SNPs) and two promoter regions in the BDNF gene were selected for genotype and methylation analysis. The role of interactions between BDNF genetic and epigenetic variations with MDD diagnosis, sex, and Childhood Trauma Questionnaire (CTQ) scores was also explored. We observed significant associations between neurocognitive performance and two BDNF SNPs (rs908867 and rs925946), an effect that was significantly mediated by methylation values at specific promoter I sites. We identified significant associations between neurocognitive results and methylation status as well as its interactions with MDD diagnosis, sex, and CTQ scores. Our results support the hypothesis that BDNF gene SNPs and methylation status, as well as their interactions with modulating factors, can influence cognition. Further studies are required to confirm the effect of BDNF variations and cognitive function in larger samples.
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In MDD, hypermethylation of the NR3C1 promoter impairs HPA-axis regulation following childhood trauma.
“hypermethylation of the NR3C1 promoter impairs hypothalamic-pituitary-adrenal (HPA)-axis regulation following childhood trauma”
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 [13]
The Discussion (page unavailable) reports that childhood abuse affects epigenetic regulation of hippocampal glucocorticoid receptor expression. It does not say that NR3C1 promoter hypermethylation impairs HPA-axis regulation in people with MDD; the paper’s own methylation analyses concern BDNF. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn MDD, hypermethylation of BDNF promoters, especially exon IV, reduces BDNF expression and impairs neuroplasticity.
“In MDD, hypermethylation of BDNF promoters, especially exon IV, reduces BDNF expression and impairs neuroplasticity”
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 [13]
The Introduction (page unavailable) reports higher BDNF promoter I and IV methylation in patients with depression and describes methylation as associated with gene silencing, while noting that it can also accompany active transcription. The Discussion (page unavailable) links promoter methylation to poorer cognitive performance at several sites. The paper does not establish that promoter IV hypermethylation reduces BDNF expression and thereby impairs neuroplasticity in MDD. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn schizophrenia, BDNF methylation is associated with cognitive impairment and negative symptoms.
“BDNF methylation is associated with cognitive impairment and negative symptoms”
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 [13]
The Discussion reports an association between BDNF promoter methylation and poorer cognitive performance in a sample of patients with major depressive disorder and healthy controls. It does not report this association in people with schizophrenia or address negative symptoms; the copy’s mention of schizophrenia is in the name of a cognitive test. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn schizophrenia, RELN hypermethylation reduces reelin expression and disrupts synaptic plasticity and neuronal migration.
“Studies in schizophrenia show that RELN hypermethylation reduces reelin expression and disrupts synaptic plasticity and neuronal migration”
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 [13]
The Introduction and Discussion address BDNF methylation and cognition, not RELN or reelin. Searches for RELN hypermethylation in schizophrenia and for reelin’s role in neuronal migration or synaptic plasticity found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn schizophrenia, COMT methylation alters dopamine metabolism.
“COMT methylation alters dopamine metabolism”
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 [13]
The Discussion describes BDNF promoter methylation and cognitive performance in patients with major depressive disorder and healthy controls. Searches for COMT methylation, dopamine metabolism, and schizophrenia found no passage addressing the attributed claim; the only schizophrenia-related passage names a cognitive test. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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References 83 · Cited by 84
- Authors
- Ferrer, A., Labad, J., Salvat-Pujol, N., Barrachina, M., Costas, J., Urretavizcaya, M., de Arriba-Arnau, A., Crespo, J. M., Soriano-Mas, C., Carracedo, Á., Menchón, J. M., & Soria, V.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Instituto de Salud Carlos III (ES)
- Complejo Hospitalario Universitario de Santiago (ES)
- Universidade de Santiago de Compostela (ES)
- Corresponding author
- Soria, Virginia
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2019-10-21
- Volume
- 9
- Issue
- 1
- Pages
- 265-265
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC6803763
- OpenAlex
- W2981164036
- Cited by
- 84
- References
- 83
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 16 · 2023: 13 · 2022: 15 · 2021: 9 · 2020: 5
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Hispana (submittedVersion, cc-by)
- Repositorio institucional da Universidade de Santiago de Compostela (University of Santiago de Compostela) (submittedVersion, cc-by)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, cc-by)
- Funders
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PI15/00662, CPII16/00019, CPII16/00048)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- brain-derived neurotrophic factor, BDNF gene, major depressive disorder, cognitive impairment, DNA methylation, single nucleotide polymorphisms, child abuse, epigenetics, gene-environment interaction, sex differences, promoter methylation
- MeSH terms
- Cognition, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Case-Control Studies, DNA Methylation, Brain-Derived Neurotrophic Factor, Polymorphism, Single Nucleotide, Epigenesis, Genetic
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