Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia
Open accessAbstract
BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances ine arly brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development. RESULTS: We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci,particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples.Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that schizophrenia-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development. CONCLUSIONS: Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects.
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EWAS studies have identified differential DNAm in HTR2A, HTR5A and HTR1E genes in those with psychosis.
“Further, EWAS studies have identified differential DNAm in HTR2A (Numata, Ye, Herman, & Lipska, 2014), HTR5A and HTR1E (Nishioka et al., 2013; Pidsley et al., 2014) genes in those with psychosis.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Pidsley et al., 2014
In Results and discussion, under identification of differentially methylated positions in the prefrontal cortex (page unavailable), the paper reports significantly different DNA methylation at HTR5A in schizophrenia patients versus controls. The cited Pidsley paper does not report an HTR1E finding in the passages retrieved for that gene. HTR2A is separately attributed to Numata et al. in the citing sentence, so it is not assessed against Pidsley. (LLM, conf=0.88)
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- Authors
- Pidsley, R., Viana, J., Hannon, E., Spiers, H., Troakes, C., Al-Saraj, S., Mechawar, N., Turecki, G., Schalkwyk, L. C., Bray, N. J., & Mill, J.
- Affiliations
- Garvan Institute of Medical Research (AU)
- University of Exeter (GB)
- King's College London (GB)
- Douglas Mental Health University Institute (CA)
- University of Essex (GB)
- Corresponding author
- Mill, Jonathan
- ORCID
- Venue
- Genome biology
- Published
- 2014-10-28
- Volume
- 15
- Issue
- 10
- Pages
- 483-483
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC4262979
- OpenAlex
- W1980511338
- Cited by
- 157
- References
- 40
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 11 · 2023: 6 · 2022: 10 · 2021: 15 · 2020: 11 · 2019: 15 · 2018: 15 · 2017: 25 · 2016: 24 · 2015: 18 · 2014: 2 · 2012: 1
- FWCI
- 9.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (G0700089, GR082557)
- National Institutes of Health
- Medical Research Council (MC_PC_15004, MR/K013807/1, K013807)
- National Institute on Aging (R01AG036039, AG036039)
- 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 › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- schizophrenia, DNA methylation, epigenetics, brain development, prefrontal cortex, cerebellum, fetal brain development, differentially methylated positions
- MeSH terms
- Brain, Cerebellum, Humans, Schizophrenia, Prefrontal Cortex, DNA Methylation, Epigenesis, Genetic, Fetal Development
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