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Stress-Related Methylation of the Catechol- O -Methyltransferase Val 158 Allele Predicts Human Prefrontal Cognition and Activity
Open accessAbstract
DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O-methyltransferase (COMT) Val(158) allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val(158) allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val(158) allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.
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“In rats, a direct correlation between catechol-O-methyltransferase (COMT) methylation in peripheral mononuclear blood cells and the prefrontal cortex was observed (Ursini et al., 2011).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Ursini et al., 2011
In the citing paper
“as several studies indicate its role in stress reactivity on a genetic [46,47] and epigenetic level [48].”
From Dynamic DNA methylation changes in the COMT gene promoter region in response to mental stress and its modulation by transcranial direct current stimulation (2021) · cites this paper as [48]
In the citing paper
“Indeed, for COMT DNAm several studies show that methylation status in peripheral tissue can serve as surrogate for brain DNAm [48,50].”
From Dynamic DNA methylation changes in the COMT gene promoter region in response to mental stress and its modulation by transcranial direct current stimulation (2021) · cites this paper as [48]
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“However, several studies found that DNA methylation can predict behavioral outcomes, including major depression, in humans (Ursini et al., 2011; Guintivano et al., 2014; Humphreys et al., 2019).”
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“…[Tunbridge et al., 2006; Pecina et al., 2014], modulate stress reaction and cognitive functions [Papaleo et al., 2008; Ren-Patterson et al., 2005; Ursini et al., 2011], and involve in several psychiatric disorders Additional Supporting Information may be found in the online version of this…”
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“Our data showed no significant difference in COMT_1 methylation when we compared the female and male subjects in this sample (Figure 4).”
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“…of one site (rs4680 Val) in the COMT gene in peripheral blood mononuclear cells negatively with lifetime stress and brain activity in prefrontal cortex, suggesting greater stress and lower methylation were related to reduced cortical efficiency in healthy participants (Ursini et al., 2011).”
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“…marks of regulatory elements of gene expression in different brain areas such as the PFC. Interestingly, higher methylation related to Val-allele was associated with decreased COMT expression in mononuclear cells and was negatively associated with childhood trauma scores (Ursini et al., 2011).”
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“Метилирование в локусе rs4680 было ассоциировано с рабочей памятью у здоровых людей [29], а метилирование в промоторе гена COMT, связанной с мембранами (MB-COMT), — с нейрональной активностью в левой дорсолатеральной префронтальной коре [30].”
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The relationship between methylation of dopamine-related genes, family environment and creativity
Zhang, S., Yang, X., Ren, J., & Zhang, J. (2021) · Advances in Psychological Science · doi:10.3724/sp.j.1042.2021.01911
“…DNA碱基序列的改变, 但是个体基因 组 DNA 碱基序列的差异可能会影响环境对于基 因组甲基化的修饰效果, 即遗传因素可能在此过 程中起调节作用。对于某一基因而言, 同一环境 因素对其甲基化修饰的效果可能会因不同个体所 携带等位基因的不同而有所不同, 进而导致对个 体心理行为的不同影响(Barker et al., 2018; Mulder et al., 2017)。以上研究发现为进一步解释环境以 及遗传与环境交互作用对个体心理行为影响的潜 在分子生物机制提供了重要的启示。 已有研究发现, 环境因素对多巴胺相关基因 甲基化的调控具有重要影响。例如, 对于 COMT 基因的研究发现,…”
Bazov, I., & Bakalkin, G. Y. (2016) · Epigenetics and human health · doi:10.1007/978-3-319-29901-3_3
Catechol-O-Methyltransferase (COMT) val158met Polymorphism as a Risk Factor for PTSD
Valente, N. L. M., Fiks, J. P., & Mello, M. F. (2016) · Springer eBooks · doi:10.1007/978-3-319-08359-9_27
Xavier, J., Bastos, C. R., Marins, T. M., Camerini, L., de Mello, D. B., Antunes, B., Quevedo, L. D. Á., de Matos, M. B., Pinheiro, R. T., & Ghisleni, G. (2023) · Research Square · doi:10.21203/rs.3.rs-2874971/v1
Xavier, J., Bastos, C. R., Marins, T. M., Camerini, L., de Mello, D. B., Antunes, B., Quevedo, L. D. Á., de Matos, M. B., Pinheiro, R. T., & Ghisleni, G. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16631
Hussein, H. K., Loarce, Y., & Barbaro, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.05.686833
Additional file 2 of Altered immune phenotype and DNA methylation in panic disorder
Petersen, C. L., Chen, J.-Q., Salas, L. A., & Christensen, B. C. (2020) · Figshare · doi:10.6084/m9.figshare.13257575
Driven by Dopamine: Genetic Insights into Motivation and Performance in Sports and Esports
Majchrzak, N., Humińska‐Lisowska, K., & Leońska‐Duniec, A. (2026) · Genes · doi:10.3390/genes17020144 · Cited by 1
Rose, M. A., Robinson, A., & Payton, A. (2026) · PLoS ONE · doi:10.1371/journal.pone.0353790
“Two individuals with identical COMT genotypes could have different cognitive trajectories due to different COMT DNA methylation over time [46]. models that do not account for this dynamic layer average across distinct states, potentially obscuring true relationships.”
Brain and cognitive correlates of FKBP5: methylation patterns in schizophrenia
Latorre-Guardia, M., Almodóvar-Payá, C., París-Gómez, I., Guardiola-Ripoll, M., Canales-Rodríguez, E. J., Fuentes‐Claramonte, P., García‐León, M. Á., Garcia‐Ruiz, B., Sotero-Moreno, A., Guerrero‐Pedraza, A., et al. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111959
Metadata
- Authors
- Ursini, G., Bollati, V., Fazio, L., Porcelli, A., Iacovelli, L., Catalani, A., Sinibaldi, L., Gelao, B., Romano, R., Rampino, A., Taurisano, P., Mancini, M., Di Giorgio, A., Popolizio, T., Baccarelli, A., De Blasi, A., Blasi, G., & Bertolino, A.
- Affiliations
- University of Bari Aldo Moro (IT)
- University of Milan (IT)
- Sapienza University of Rome (IT)
- Casa Sollievo della Sofferenza (IT)
- Harvard University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-05-04
- Volume
- 31
- Issue
- 18
- Pages
- 6692-6698
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6632869
- OpenAlex
- W2008679805
- Cited by
- 188
- References
- 61
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 12 · 2020: 14 · 2019: 10 · 2018: 9 · 2017: 17 · 2016: 25 · 2015: 13 · 2014: 20 · 2013: 16 · 2012: 22
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- catechol-O-methyltransferase, DNA methylation, CpG, working memory, prefrontal cortex, gene silencing, epigenetics, peripheral blood mononuclear cells, gene expression, enzyme activity, rats
- MeSH terms
- Adult, Alleles, Animals, Catechol O-Methyltransferase, Cognition, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Memory, Short-Term, Neuropsychological Tests, Polymorphism, Genetic, Surveys and Questionnaires, Stress, Psychological, Blotting, Western, Rats, Wistar, Prefrontal Cortex, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Rats
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