Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset
Abstract
Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome‐wide (global) and gene‐specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia ( P <2.0×10 ‐6 ) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R 2 =0.11, ANOVA P >0.001). Specifically, haloperidol was associated with higher (“control‐like”) methylation ( P =0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation ( P =0.002). With regard to the gene‐specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S‐COMT was hypermethylated in patients with schizophrenia ( P =0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early‐onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA‐methylation signatures show promise of serving as a schizophrenia biomarker in the future.—Melas, P. A., Rogdaki, M., Ösby, U., Schalling, M., Lavebratt, C., Ekström, T. J. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J. 26, 2712‐2718 (2012). www.fasebj.org
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Haloperidol affects DNA methylation in leucocytes of schizophrenia patients.
“Haloperidol affects DNAm in leucocytes of SCZ patients (Melas et al., 2012)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Melas et al., 2012
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Jaenisch, R., & Bird, A. (2003) · Nature Genetics · doi:10.1038/ng1089 · Cited by 6,325 · see citing works
Epigenetic regulation in psychiatric disorders
Tsankova, N., Renthal, W., Kumar, A., & Nestler, E. J. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2132 · Cited by 1,400 · see citing works
Shimabukuro, M., Sasaki, T., Imamura, A., Tsujita, T., Fuke, C., Umekage, T., Tochigi, M., Hiramatsu, K., Miyazaki, T., Oda, T., et al. (2007) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2006.08.006 · Cited by 108 · see citing works
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Epigenetic basis of mental illness
Nestler, E. J., Peña, C. J., Kundakovic, M., Mitchell, A., & Akbarian, S. (2016) · The Neuroscientist · doi:10.1177/1073858415608147 · Cited by 342 · see citing works
Walton, E., Hass, J., Liu, J., Roffman, J. L., Bernardoni, F., Roessner, V., Kirsch, M., Schackert, G., Calhoun, V., & Ehrlich, S. (2016) · Schizophrenia Bulletin · doi:10.1093/schbul/sbv074 · Cited by 286 · see citing works
BECon: a tool for interpreting DNA methylation findings from blood in the context of brain
Edgar, R. D., Jones, M. J., Meaney, M. J., Turecki, G., & Kobor, M. S. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.171 · Cited by 261 · see citing works
Aberg, K. A., McClay, J. L., Nerella, S., Clark, S., Kumar, G., Chen, W., Khachane, A. N., Xie, L., Hudson, A., Gao, G., et al. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.3730 · Cited by 248 · see citing works
Smigielski, L., Jagannath, V., Rössler, W., Walitza, S., & Grünblatt, E. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0601-3 · Cited by 168 · see citing works
Misiak, B., Szmida, E., Karpiński, P., Loska, O., Sąsiadek, M. M., & Frydecka, D. (2015) · Epigenomics · doi:10.2217/epi.15.68 · Cited by 77 · see citing works
Reelin (RELN) DNA methylation in the peripheral blood of schizophrenia
Nabil Fikri, R. M., Norlelawati, A. T., Nour El-Huda, A. R., Hanisah, M. N., Kartini, A., Norsidah, K., & Nor Zamzila, A. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.12.020 · Cited by 61 · see citing works
Male-Specific Association between Dopamine Receptor D4 Gene Methylation and Schizophrenia
Cheng, J., Wang, Y., Zhou, K., Wang, L., Li, J., Zhuang, Q., Xu, X., Xu, L., Zhang, K., Dai, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089128 · Cited by 60 · see citing works
Zhou, J., Li, M., Wang, X., He, Y., Xia, Y., Sweeney, J. A., Kopp, R. F., Liu, C., & Chen, C. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.674273 · Cited by 56 · see citing works
Can epigenetics shine a light on the biological pathways underlying major mental disorders?
Alameda, L., Trotta, G., Quigley, H., Rodriguez, V., Gadelrab, R., Dwir, D., Dempster, E., Wong, C. C. Y., & Forti, M. D. (2022) · Psychological Medicine · doi:10.1017/s0033291721005559 · Cited by 60 · see citing works
“…have investigated the effect of antipsychotic medication, have shown, on the one hand, that Haloperidol affects DNAm in leucocytes of SCZ patients (Melas et al., 2012), while on the other hand, a recent EWAS study showed that Clozapine exposure leads to DNAm differences in patients with…”
BackgroundResultInfluentialEpigenetics and gene expression profile in first-episode psychosis: the role of childhood trauma
Tomassi, S., & Tosato, S. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.10.018 · Cited by 51 · see citing works
Gao, S., Cheng, J., Li, G., Sun, T., Xu, Y., Wang, Y., Du, X., Xu, G., & Duan, S. (2017) · European Psychiatry · doi:10.1016/j.eurpsy.2017.03.002 · Cited by 39 · see citing works
- Authors
- Melas, P. A., Rogdaki, M., Ösby, U., Schalling, M., Lavebratt, C., & Ekström, T. J.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Lavebratt, Catharina
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2012-03-16
- Volume
- 26
- Issue
- 6
- Pages
- 2712-2718
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2077472315
- Cited by
- 186
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 15 · 2021: 18 · 2020: 12 · 2019: 14 · 2018: 11 · 2017: 19 · 2016: 11 · 2015: 15 · 2014: 28 · 2013: 19 · 2012: 11
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Bodossaki Foundation
- Vetenskapsrådet
- Stockholms Läns Landsting
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, DNA methylation, global DNA hypomethylation, epigenetics, antipsychotic drugs, haloperidol, early-onset schizophrenia, catechol-O-methyltransferase, leukocytes, biomarkers
- MeSH terms
- Adolescent, Adult, Catechol O-Methyltransferase, Female, Haloperidol, Humans, Leukocytes, Male, Middle Aged, Schizophrenia, Antipsychotic Agents, Biomarkers, Age of Onset, DNA Methylation, Epigenesis, Genetic
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