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

• Published in: Nature neuroscience 2019-02, Vol.22 (2), p.307-316
• Main Authors: Rizzardi, Lindsay F., Hickey, Peter F., Rodriguez DiBlasi, Varenka, Tryggvadóttir, Rakel, Callahan, Colin M., Idrizi, Adrian, Hansen, Kasper D., Feinberg, Andrew P.
• Format: Article
• Language: English
• Subjects: 13/31; 38/22; 38/23; 45/90; 45/91; 631/114; 631/208/176/1988; 631/208/177; 631/378/2584; Accessibility; Addictive behaviors; Animal Genetics and Genomics; Behavior, Addictive - genetics; Behavior, Addictive - metabolism; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Bisulfite; Brain; Brain - metabolism; Chromatin; Chromatin - metabolism; CpG Islands; Deoxyribonucleic acid; DNA; DNA Methylation; DNA sequencing; Epigenesis, Genetic; Epigenetics; Gene expression; Genome; Genomes; Heritability; Humans; Mental disorders; Neurobiology; Neurons - metabolism; Neurosciences; Neurosis; Neuroticism - physiology; Nucleus accumbens; Prefrontal cortex; Regulatory sequences; Resource; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Transcription
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-018-0297-8

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 both CpG and non-CpG methylation (CG-DMRs and CH-DMRs) only in neuronal cells across brain regions. Neuronal CH-DMRs were highly associated with differential gene expression, whereas 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, thus suggesting a mechanistic link between pathology and differential neuron-specific epigenetic regulation in distinct brain regions. An extensive profile of DNA methylation in neuronal and non-neuronal cells across four brain regions is reported, showing that differential epigenetic marks are enriched for DNA variants associated with neuropsychiatric traits.