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Nat Neurosci. 2016 Jan;19(1):40-7. doi: 10.1038/nn.4181. Epub 2015 Nov 30.

Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex.

Author information

1
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland, USA.
2
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
3
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
4
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
5
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
6
Department of Neuroscience and the Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

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.

PMID:
26619358
PMCID:
PMC4783176
DOI:
10.1038/nn.4181
[Indexed for MEDLINE]
Free PMC Article

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