We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n=166) of human fetal brain samples spanning 56-166 days post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs are primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and show significant overlap with genetic variants also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum) we show that most fetal brain mQTLs are developmentally stable, although a subset is characterized by fetal-specific effects. We show that fetal brain mQTLs are 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 demonstrate how mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.
Schematic of mQTLs in genomic region: 1:2322054-2452501, making plot
If approporiate the top of the figure is the gene track, where each gene is located on a separate line with the thicker black bars indicating exons. Each gene is annotannotated with it's Entrez ID, and the red arrows indicate the direction of transcription. Vertical blue lines indicate locations of all variants tested and vertical red lines indicate locations of all DNA methylation probes tested. Significant mQTLs (P < 3.60 x 10-13) are indicated by black lines between the respective variant and DNA methylation probe, where the line width reflects the magnitude of the effect.
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