Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex
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Abstract
DNA methylation (DNAm) is important in brain development and is potentially important in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape and overlap regions of genetic risk for schizophrenia. A quarter of published genome-wide association studies (GWAS)-suggestive loci (4,208 of 15,930, P < 10(-100)) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder.
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“Although less well characterized, histone modi fi cations also affect COMT expression, and the general mechanisms such as histone acetylation and methylation are known to in fl uence gene expression in neuropsychiatric contexts (82).”
- Authors
- Jaffe, A. E., Gao, Y., Deep-Soboslay, A., Tao, R., Hyde, T. M., Weinberger, D. R., & Kleinman, J. E.
- Affiliations
- Johns Hopkins University (US)
- Lieber Institute for Brain Development (US)
- Corresponding author
- Jaffe, Andrew E
- Venue
- Nature Neuroscience
- Published
- 2015-11-30
- Volume
- 19
- Issue
- 1
- Pages
- 40-47
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4783176
- OpenAlex
- W2181445041
- Cited by
- 511
- References
- 72
- Citations by year
- 2026: 21 · 2025: 35 · 2024: 47 · 2023: 41 · 2022: 55 · 2021: 59 · 2020: 55 · 2019: 53 · 2018: 53 · 2017: 53 · 2016: 35 · 2015: 4
- FWCI
- 20.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Commonwealth of Virginia
- National Institute of Mental Health (R21MH102791)
- 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, frontal cortex, brain development, methylation quantitative trait loci, epigenetics, human brain
- MeSH terms
- Genotype, Humans, Human Development, Schizophrenia, Tissue Banks, Prefrontal Cortex, Age of Onset, CpG Islands, DNA Methylation, Epigenesis, Genetic, Fetal Development, Genetic Loci, Transcriptome
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