While epigenetic marks drive traits on their own, their complex influence on phenotype can also be caught in an intimate tango with underlying sequence. One way to characterize this association is by studying DNA methylation quantitative trait loci (mQTLs), which are SNPs in the genome that influence DNA methylation.
Previously, the Lab of Jonathan Mill at the University of Exeter Medical School and King’s College London charted how the methylome of the brain changes during neurodevelopment in each sex and noticed a surprising overlap between distinct methylation modules and loci associated with psychiatric disorders like schizophrenia and autism. Now the team set out to examine how these DNA methylation patterns interact with genetic variation.
Here’s what they found in 166 human fetal brain samples (56-166 days post-conception) using bead-chip arrays for both DNA methylation and SNPs:
- mQTLs are widespread in the fetal brain with over 16,000 associated pairs of methylated sites and SNPs.
- Fetal mQTLs are primarily cis-acting, but there were also some notable trans-acting mQTLs showcasing the long-range interactions in the genome.
- Using ENCODE data, they found that the mQTLs were enriched in repressive chromatin marks (H3K9me3 and H3K27me3), and were significantly depleted in activating marks (H3K4me3 and H3K36me3). The mQTLs were also enriched in signs of open chromatin, including DNase hypersensitive sites, and transcription factor binding sites, such as CTCF sites.
- Comparison with the adult brain (prefrontal cortex, striatum and cerebellum) showed that most fetal mQTLs were developmentally stable, although a subset was fetal specific.
- mQTLs substantially overlapped with SNPs associated with regulating gene expression in the adult brain.
- Interestingly, the fetal mQTLs were enriched in risk loci identified by a recent large scale schizophrenia GWAS.
- Showing off the power of integrated data, the team demonstrated how the mQTLs could be used to refine GWAS loci by honing in and providing some putative casual evidence.
First author Eilis Hannon shares, “This data is particularly relevant for disorders such as schizophrenia, where it is thought that changes early in brain development increase an individual’s susceptibility to develop the illness later on in life. Therefore, understanding the genetic effects of risk variants on gene regulation during the earliest stages of brain development may point us towards the underlying biology of schizophrenia.”
Senior author Jonathan Mill concludes, “This study builds on the tremendous advances in identifying the genetic risks for schizophrenia in the last couple of years. We have shown that genetic variation can have significant effects on gene regulation during brain development, with important implications for understanding the origins of schizophrenia and other disorders with a neurodevelopmental component.”