Mapping DNA Methylation Signatures to Identify Epigenetic Variation Across Subcortical Regions of the Human Posttraumatic Stress Disorder Brain

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BACKGROUND: Posttraumatic stress disorder (PTSD) is a mental disorder that may occur in the aftermath of severe psychological trauma. Epigenetic changes in the brain may play a critical role in understanding the neurobiology of PTSD by linking environmental traumatic stress exposure to lasting alterations in gene expression that shape neuronal function. METHODS: We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypical controls and PTSD and major depressive disorder (MDD) cases across 6 regions implicated in the fear circuitry of the brain. We performed RNA sequencing (RNA-seq) to examine changes in gene expression and linked these changes to changes in DNAm at nearby sites in a case-control manner. We created a single cell-type atlas of DNAm using a single-nucleus RNA-seq reference panel to map epigenetic changes to specific cell types. Finally, we leveraged a human PTSD ketamine trial to associate blood DNAm biomarkers of ketamine efficacy with specific changes in DNAm in the brain. RESULTS: We found significant differential methylation for PTSD near 195 genes, and to further resolve the changes we observed, we constructed a cell type-specific DNAm atlas defined for changes to the PTSD methylome across 6 cell types. To identify potential therapeutic intersections for PTSD, we found significant methylation levels in the MAD1L1, ELFN1, and WNT5A genes in patients with PTSD who responded to ketamine. Finally, to better understand the unique biology of PTSD, we analyzed matching methylation data for a cohort of donors with MDD with no known history of trauma or PTSD. CONCLUSIONS: Our results implicate DNAm as an epigenetic mechanism underlying the molecular changes associated with the subcortical fear circuitry of the PTSD brain.

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