Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia
Abstract
The catechol-o-methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB-COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S-COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated.
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For COMT DNAm, several studies show that methylation status in peripheral tissue can serve as a surrogate for brain DNAm.
“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 [50]
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- Authors
- Murphy, B. C., O'Reilly, R. L., & Singh, S. M.
- Affiliations
- Western University (CA)
- Corresponding author
- Singh, Shiva M.
- ORCID
- Singh, Shiva M.
- Venue
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2005-01-05
- Volume
- 133B
- Issue
- 1
- Pages
- 37-42
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W2138509390
- Cited by
- 102
- References
- 35
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 7 · 2019: 2 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 11
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- 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
- catechol-O-methyltransferase, DNA methylation, cytosine methylation, schizophrenia, epigenetics, brain regions, blood DNA, monozygotic twins, candidate genes, negative symptoms
- MeSH terms
- Adult, Base Sequence, Brain, Catechol O-Methyltransferase, Cytosine, DNA, DNA Mutational Analysis, Humans, Molecular Sequence Data, Ontario, Promoter Regions, Genetic, Schizophrenia, Twins, Monozygotic, CpG Islands, DNA Methylation, Polymorphism, Single Nucleotide
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