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Nat Neurosci. 2016 Jan;19(1):48-54. doi: 10.1038/nn.4182. Epub 2015 Nov 30.

Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.

Author information

1
University of Exeter Medical School, University of Exeter, Exeter, UK.
2
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
3
Garvan Institute of Medical Research, Sydney, NSW, Australia.
4
Douglas Mental Health Institute, McGill University, Montreal, QC, Canada.
5
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
6
School of Biological Sciences, University of Essex, Colchester, UK.

Abstract

We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.

PMID:
26619357
PMCID:
PMC4714325
DOI:
10.1038/nn.4182
[Indexed for MEDLINE]
Free PMC Article

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