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Cell type-specific epigenetic links to schizophrenia risk in the brain

Mendizabal, Isabel, Berto, Stefano, Usui, Noriyoshi, Toriumi, Kazuya, Chatterjee, Paramita, Douglas, Connor, Huh, Iksoo, Jeong, Hyeonsoo, Layman, Thomas, Tamminga, Carol A., Preuss, Todd M., Konopka, Genevieve, Yi, Soojin V.
Genome biology 2019 v.20 no.1 pp. 135
DNA methylation, brain, epigenetics, high-throughput nucleotide sequencing, neurons, oligodendroglia, patients, risk, schizophrenia, tissues, transcriptome
BACKGROUND: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. RESULTS: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. CONCLUSIONS: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.