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

Eilis Hannon, Helen Spiers, Joana Viana, Ruth Pidsley, Joe Burrage, Therese M. Murphy, Claire Troakes, Gustavo Turecki, Michael C. O'Donovan, Leonard C. Schalkwyk, Nicholas J. Bray, Jonathan Mill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

237 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)48-54
JournalNature Neuroscience
Volume19
Issue number1
Early online date30 Nov 2015
DOIs
Publication statusPublished - 31 Jan 2016

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