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Abstract
Brain cellular heterogeneity may bias cell type specific DNA methylation patterns, influencing findings in psychiatric epigenetic studies. We performed fluorescence activated cell sorting (FACS) of neuronal nuclei and Illumina HM450 DNA methylation profiling in post mortem frontal cortex of 29 major depression and 29 matched controls. We identify genomic features and ontologies enriched for cell type specific epigenetic variation. Using the top cell epigenotype specific (CETS) marks, we generated a publically available R package, “CETS,” capable of quantifying neuronal proportions and generating in silico neuronal profiles from DNA methylation data. We demonstrate a significant overlap in major depression DNA methylation associations between FACS separated and CETS model generated neuronal profiles relative to bulk profiles. CETS derived neuronal proportions correlated significantly with age in the frontal cortex and cerebellum and accounted for epigenetic variation between brain regions. CETS based control of cellular heterogeneity will enable more robust hypothesis testing in the brain.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Author Contributions
Study design: Z.K.; laboratory experiments: J.G.; statistical analysis: Z.K. and M.A.
Acknowledgments
Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders and the University of Maryland, Baltimore, MD. This work was funded by NIMH 1R21MH094771-01. We would like to further thank The Solomon R. and Rebecca D. Baker Foundation for their generous support of this research.