Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder
Open accessAbstract
The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.
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Hypomethylation of the COMT membrane-bound isoform has been identified in samples of people with SCZ across tissues, while the soluble isoform (S-COMT) has been reported to be hypermethylated.
“Hypomethylation of the COMT membrane-bound isoform, has been identified in samples of people with SCZ across tissues (Abdolmaleky et al., 2006; Nohesara et al., 2011; Nour El Huda et al., 2018; Walton et al., 2014), while the soluble isoform (S-COMT) has been reported to be hypermethylated (Melas et al., 2012; Murphy, O'Reilly, & Singh, 2005).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Abdolmaleky et al., 2006
The MB-COMT promoter methylation results report significantly less methylation in schizophrenia patients than in controls, particularly in the left frontal lobe. This paper examined post-mortem frontal brain tissue, so it does not by itself establish the citing clause’s “across tissues” qualification. The S-COMT statement is attached to different citations and is not attributed to this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredStudies investigating human brain tissue confirm that both hypo- and hyper-methylation of DNA are associated with AD.
“Studies investigating human brain tissue confirm that both hypo– and hyper-methylation of DNA are associated with AD17,18.”
From Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice (2021) · cites this paper as [17]
The Results (page unavailable) describe post-mortem human brain tissue from patients with schizophrenia and controls and report MB-COMT promoter hypomethylation in schizophrenia and bipolar disorder. The Introduction (page unavailable) also describes reelin-gene hypermethylation in schizophrenia. These passages support the brain-tissue and methylation aspects, but not the claimed association with AD. (LLM, conf=0.86)
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- Authors
- Abdolmaleky, H. M., Cheng, K.-H., Faraone, S. V., Wilcox, M., Glatt, S. J., Gao, F., Smith, C. L., Shafa, R., Aeali, B., Carnevale, J., Pan, H., Papageorgis, P., Ponte, J. F., Sivaraman, V., Tsuang, M. T., & Thiagalingam, S.
- Affiliations
- Boston University (US)
- SUNY Upstate Medical University (US)
- University of California San Diego (US)
- MetroWest Medical Center (US)
- University of Maryland, Baltimore (US)
- Harvard University (US)
- Corresponding author
- Abdolmaleky, Hamid Mostafavi
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-19
- Volume
- 15
- Issue
- 21
- Pages
- 3132-3145
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2799943
- OpenAlex
- W2128025482
- Cited by
- 462
- References
- 93
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 12 · 2022: 8 · 2021: 23 · 2020: 12 · 2019: 13 · 2018: 17 · 2017: 25 · 2016: 32 · 2015: 29 · 2014: 43 · 2013: 32 · 2012: 39
- FWCI
- 16.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stanley Medical Research Institute
- Iran University of Medical Sciences
- National Institutes of Health
- National Institute of Mental Health (R25MH060485)
- National Cancer Institute (R01CA101773)
- National Institute of Environmental Health Sciences (R01ES010377)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- 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
- Keywords
- promoter methylation, promoter hypomethylation, schizophrenia, bipolar disorder, COMT Val158Met polymorphism, gene expression, dopamine D1 receptor, dopamine degradation, frontal lobe, epigenetics, postmortem brain, risk factors
- MeSH terms
- Alcoholism, Bipolar Disorder, Catechol O-Methyltransferase, Frontal Lobe, Heart Diseases, Humans, Polymorphism, Genetic, Promoter Regions, Genetic, Risk Factors, Schizophrenia, Antipsychotic Agents, Case-Control Studies, Receptors, Dopamine D1, CpG Islands, DNA Methylation, Amino Acid Substitution, Genetic Predisposition to Disease, Epigenesis, Genetic
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.
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