Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions
Open accessAbstract
Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease.
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These inflation values are comparable to those obtained in other recent large-scale EWAS.
“These values are comparable to those obtained in other recent large-scale EWAS [49]”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [49]
DNA hypermethylation of DRD2 promoter regions, such as in exon 1 or upstream CpG islands, downregulates receptor expression; hypomethylation increases DRD2 levels thereby altering dopamine sensitivity.
“DNA hypermethylation of DRD2 promoter regions, such as in exon 1 or upstream CpG islands, downregulates receptor expression; on the contrary, hypomethylation increases DRD2 levels thereby altering dopamine sensitivity”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [114]
The Results section reports schizophrenia-associated methylation differences at loci including RPH3AL, and the Discussion notes a general role for epigenetic processes in gene expression (page numbers unavailable). Searches for DRD2, its promoter and the proposed effects on receptor expression and dopamine sensitivity found no passage addressing the claim. (LLM, conf=0.76)
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Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment
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Sex-specific DNA methylation differences in Alzheimer’s disease pathology
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“[32] developed a Bayesian method that estimates inflation in EWAS based on empirical null distributions, which is implemented in the Bioconductor package bacon.”
ResultInfluentialAccelerated aging in the brain, epigenetic aging in blood, and polygenic risk for schizophrenia
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DNA methylation age is not accelerated in brain or blood of subjects with schizophrenia
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Molecular windows into the human brain for psychiatric disorders
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Epigenetic clock analysis of blood samples from Japanese schizophrenia patients
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Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches
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Map of epigenetic age acceleration: A worldwide analysis
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Biological aging in schizophrenia and psychosis severity: DNA methylation analysis
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Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex
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Methylation age acceleration does not predict mortality in schizophrenia
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Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia
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Peripheral Blood-Based Gene Expression Studies in Schizophrenia: A Systematic Review
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Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults
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Longitudinal investigation of DNA methylation changes preceding adolescent psychotic experiences
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Cortical cellular diversity and development in schizophrenia
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A New Era for Epigenetic Epidemiology
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Ori, A. P. S., Loohuis, L. M. O., Guintivano, J., Hannon, E. J., Dempster, E. L., Clair, D. S., Bass, N. J., McQuillin, A., Mill, J. S., Sullivan, P. F., et al. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01660-8 · Cited by 26 · see citing works
Comparative analysis reveals distinctive epigenetic features of the human cerebellum
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Schizophrenia is associated with altered DNA methylation variance
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Epigenetic clocks in relapse after a first episode of schizophrenia
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Integrative In Silico Analysis of Genome-Wide DNA Methylation Profiles in Schizophrenia
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Schizophrenia: a classic battle ground of nature versus nurture debate
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Variability of DNA Methylation within Schizophrenia Risk Loci across Subregions of Human Hippocampus
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Development of a novel epigenetic clock resistant to changes in immune cell compositionPreprint
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Methylomic signature of current cannabis use in two first-episode psychosis cohorts
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Epigenetics of Ageing and Psychiatric Disorders
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Epigenetics: a missing link in understanding psychiatric disorders?
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Genome-wide DNA methylation profiles of autism spectrum disorder
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Epigenetic studies of schizophrenia: current status and future directions
Migdalska‐Richards, A., & Mill, J. S. (2019) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.12.003 · Cited by 9 · see citing works
DNA Methylation Differences in Cortical Grey and White Matter in Schizophrenia
van Berlekom, A. B., Notman, N., Sneeboer, M. A. M., Snijders, G. J. L., Houtepen, L. C., Nispeling, D. M., He, Y., Dracheva, S. M., Hol, E. M., Kahn, R. S., et al. (2021) · Epigenomics · doi:10.2217/epi-2021-0077 · Cited by 9 · see citing works
Properties of the epigenetic clock and age accelerationPreprint
Khoury, L. Y. E., Gorrie-Stone, T. J., Smart, M., Hughes, A., Bao, Y., Andrayas, A., Burrage, J., Hannon, E. J., Meena Kumari, B., Mill, J. S., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/363143 · Cited by 8 · see citing works
Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus
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30 SCHIZOPHRENIA IS CHARACTERIZED BY AGE- AND SEX-SPECIFIC EFFECTS ON EPIGENETIC AGING
Ori, A. P. S., Loohuis, L. M. O., Guintivano, J., Clair, D. S., McQuillin, A., Mill, J. S., Sullivan, P. F., Kahn, R. S., Horvath, S., & Ophoff, R. A. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2019.07.171 · Cited by 6 · see citing works
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Clifton, N. E., Policicchio, S. S. S., Walker, E., Castanho, I., Bosworth, M. L., Saravanaraj, K. S., Burrage, J., Hall, J., Dempster, E. L., Hannon, E. J., et al. (2025) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaf091 · Cited by 6 · see citing works
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A brain DNA co‐methylation network analysis of psychosis in Alzheimer's disease
Kouhsar, M. P., Weymouth, L. S., Smith, A. R., Imm, J. L., Bredemeyer, C., Wedatilake, Y., Torkamani, A., Bergh, S., Selbæk, G., Mill, J. S., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14501 · Cited by 8 · see citing works
Алфимова, М. В., Kondratyev, N. V., Golov, A. K., & Голимбет, В. Е. (2020) · Scientific Reports · doi:10.1038/s41598-020-61671-2 · Cited by 6 · see citing works
Map of epigenetic age acceleration: a worldwide meta-analysisPreprint
Yusipov, I., Kalyakulina, A., Franceschi, C., & Ivanchenko, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.17.585398 · Cited by 6 · see citing works
Intergenerational transmission of complex traits and the offspring methylome
Hagenbeek, F., Pool, R., Asselt, A. V. V., Ehli, E., Smit, A., Bartels, M., Hottenga, J., Dolan, C. V., van Dongen, J., & Boomsma, D. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02981-7 · Cited by 1 · see citing works
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Network-Based Analysis of Cognitive Impairment and Memory Deficits from Transcriptome Data
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Epigenetic Control in Schizophrenia
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Epigenetic epidemiology of psychiatric disorders
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The Role of Epigenetics in the Developmental Origins of Health and Disease
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Correlation of Alzheimer’s Disease and Other Psychological and Non-Psychological Conditions
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‘Almost nothing is firmly established’: A History of Heredity and Genetics in Mental Health Science
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Epigenetics in mental and neurodegenerative disorders
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The biology of schizophrenia as a neurodevelopmental disorder
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- Authors
- Viana, J., Hannon, E., Dempster, E., Pidsley, R., Macdonald, R., Knox, O., Spiers, H., Troakes, C., Al-Saraj, S., Turecki, G., Schalkwyk, L. C., & Mill, J.
- Affiliations
- University of Exeter (GB)
- Garvan Institute of Medical Research (AU)
- King's College London (GB)
- McGill University (CA)
- University of Essex (GB)
- Corresponding author
- Mill, Jonathan
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-12-22
- Volume
- 26
- Issue
- 1
- Pages
- ddw373
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5351932
- OpenAlex
- W2563293289
- Cited by
- 105
- References
- 67
- Citations by year
- 2025: 6 · 2024: 14 · 2023: 6 · 2022: 10 · 2021: 19 · 2020: 14 · 2019: 16 · 2018: 11 · 2017: 9
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Research Exeter (University of Exeter) (publishedVersion, cc-by)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Figshare (submittedVersion)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Funders
- Research Councils UK (MR/K013807/1)
- National Institutes of Health
- Medical Research Council (MR/L016397/1, MR/K013807/1, K013807)
- National Institute on Aging (R01AG036039)
- H2020 European Research Council
- 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
- schizophrenia, DNA methylation, epigenetics, polygenic risk score, differentially methylated regions, postmortem brain, prefrontal cortex, striatum, hippocampus, cerebellum, complex disease genetics
- MeSH terms
- Adult, Brain, Cadaver, Cerebellum, Corpus Striatum, Female, Hippocampus, Humans, Male, Middle Aged, Risk Factors, Schizophrenia, Biomarkers, Case-Control Studies, Prefrontal Cortex, DNA Methylation, Multifactorial Inheritance, 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.
What counts as a claim ›How we measure confidence ›How we check this ›
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