Neuronal brain region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability

Epigenetic modifications confer stable transcriptional patterns in the brain and both normal and abnormal brain function involve specialized brain regions. We examined DNA methylation by whole genome bisulfite sequencing in neuronal and non-neuronal populations from four brain regions (anterior cingulate gyrus, hippocampus, prefrontal cortex, and nucleus accumbens) as well as chromatin accessibility in the latter two. We find pronounced differences in CpG and non-CpG differentially methylated regions (CG- and CH-DMRs) only in neuronal cells across regions. While neuronal CH-DMRs were highly associated with differential gene expression, CG-DMRs were consistent with chromatin accessibility and enriched for regulatory regions. These CG-DMRs comprise ~12 Mb of the genome that is highly enriched for genomic regions associated with heritability of neuropsychiatric traits including addictive behavior, schizophrenia, and neuroticism, suggesting a mechanistic link between pathology and differential neuron-specific epigenetic regulation in distinct brain regions.