Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major Psychosis
Open accessAbstract
Epigenetic misregulation is consistent with various non-Mendelian features of schizophrenia and bipolar disorder. To date, however, few studies have investigated the role of DNA methylation in major psychosis, and none have taken a genome-wide epigenomic approach. In this study we used CpG-island microarrays to identify DNA-methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex we find evidence for psychosis-associated DNA-methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA-methylation changes in a significant proportion of these loci correspond to reported changes of steady-state mRNA level associated with psychosis. Gene-ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in both the brain and the germline of affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. We also report evidence for a strong correlation between DNA methylation in the MEK1 gene promoter region and lifetime antipsychotic use in schizophrenia patients. Finally, we observe that frontal-cortex DNA methylation in the BDNF gene is correlated with genotype at a nearby nonsynonymous SNP that has been previously associated with major psychosis. Our data are consistent with the epigenetic theory of major psychosis and suggest that DNA-methylation changes are important to the etiology of schizophrenia and bipolar disorder.
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The breadth of coverage of epigenome-wide association studies offers more informative insight on biological pathways than the candidate gene approach.
“While both designs have their advantages and limitations, the breadth of coverage of EWAS offers a more informative insight on biological pathways. This is based on the rational that chromatin conformation and transcriptional regulation are influenced by a set of methylated or unmethylated cytosines across a region, rather than specific CpG sites in isolation (Mill et al., 2008)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Mill et al., 2008
Mill and colleagues performed the first EWAS in post-mortem brains of SCZ and BD subjects compared to controls, and found DNAm changes associated with SCZ and BD at loci involved in glutamatergic and GABAergic neurotransmission.
“In terms of EWAS Mill and colleagues (Mill et al., 2008) performed the first EWAS in post-mortem brains of SCZ and BD subjects compared to controls, and found DNAm changes associated with SCZ and BD at loci involved in glutamatergic (GRIA 2, GRIND3B) and GABAergic (MARLIN-1, KCNJ6, HELT) neurotransmission, supporting previous candidate genes results.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Mill et al., 2008
It is known that schizophrenia patients have upregulated genes for inflammatory cytokines, and downregulated Bdnf gene transcription.
“It is known that schizophrenia patients have upregulated genes for inflammatory cytokines [122, 123], and downregulated Bdnf gene transcription [124, 125].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [124]
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Self-citationProspects for epigenetic epidemiology
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“88 94 – 97 Another study comparing DNA methylation across the whole genome in live human brain tissue with that in peripheral (blood, saliva, and buccal) tissues concluded that the patterns unique to the target genomic region must be considered when selecting the best surrogate tissue to mimic…”
BackgroundAn epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
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Epigenetics of stress adaptations in the brain
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Reelin and neuropsychiatric disorders
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Association of DNA methylation differences with schizophrenia in an Epigenome-Wide association study
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DNA methylation of the BDNF gene and its relevance to psychiatric disorders
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Epigenetic signaling in psychiatric disorders: stress and depression
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Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia
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Epigenetic Signaling in Psychiatric Disorders
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Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques
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Allele-specific methylation in the human genome: Implications for genetic studies of complex disease
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Self-citationMonoamine oxidase A gene DNA hypomethylation - A risk factor for panic disorder?
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Epigenetic Research in Neuropsychiatric Disorders: the “Tissue Issue”
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Self-citationHistone modifications, DNA methylation, and Schizophrenia
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Current status and future prospects for epigenetic psychopharmacology
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Self-citationEnvironmental regulation of the neural epigenome
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Sex Differences in Brain Epigenetics
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Self-citationMale-Specific Association between Dopamine Receptor D4 Gene Methylation and Schizophrenia
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“This is based on the rational that chromatin conformation and transcriptional regulation are influenced by a set of methylated or unmethylated cytosines across a region, rather than specific CpG sites in isolation (Mill et al., 2008) Different biological pathways have been implicated in the aetio-pathogenesis across m…”
BackgroundMethodResultInfluentialEpigenetics in bipolar disorder: a critical review of the literature
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Self-citation<i>NTRK2</i> methylation is related to reduced PTSD risk in two African cohorts of trauma survivors
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- Authors
- Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., Jia, P., Assadzadeh, A., Flanagan, J., Schumacher, A., Wang, S.-C., & Petronis, A.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 82
- Issue
- 3
- Pages
- 696-711
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2427301
- OpenAlex
- W2121471393
- Cited by
- 773
- References
- 76
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 13 · 2023: 15 · 2022: 18 · 2021: 26 · 2020: 25 · 2019: 28 · 2018: 35 · 2017: 44 · 2016: 52 · 2015: 52 · 2014: 80 · 2013: 76 · 2012: 75
- FWCI
- 30.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH074127, R01MH088413)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- DNA methylation, schizophrenia, bipolar disorder, frontal cortex, CpG islands, glutamatergic neurotransmission, GABAergic neurotransmission, brain development, mitochondrial function, stress response, antipsychotic use, brain-derived neurotrophic factor, non-synonymous SNPs, gene expression
- MeSH terms
- Adult, Base Sequence, Bipolar Disorder, Brain, Female, Genes, Humans, Male, Middle Aged, Molecular Sequence Data, Schizophrenia, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Epigenesis, Genetic
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