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

TitleMethylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
Publication TypeJournal Article
Year of Publication2016
AuthorsHannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, Troakes C, Turecki G, O'Donovan MC, Schalkwyk LC, Bray NJ, Mill J
JournalNat Neurosci
Volume19
Issue1
Pagination48-54
Date Published2016 Jan
ISSN1546-1726
KeywordsAdult, Brain, Cerebellum, DNA Methylation, Epigenesis, Genetic, Female, Fetus, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Neostriatum, Polymorphism, Single Nucleotide, Prefrontal Cortex, Quantitative Trait Loci, Risk, Schizophrenia, Tissue Banks
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.

DOI10.1038/nn.4182
Alternate JournalNat. Neurosci.
PubMed ID26619357
PubMed Central IDPMC4714325
Grant ListMR/L010674/1 / / Medical Research Council / United Kingdom
AG036039 / AG / NIA NIH HHS / United States
MR/K013807/1 / / Medical Research Council / United Kingdom
G0700089 / / Medical Research Council / United Kingdom
099175/Z/12/Z / / Wellcome Trust / United Kingdom
R01 AG036039 / AG / NIA NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
G0800509 / / Medical Research Council / United Kingdom

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