BACKGROUND: Post-traumatic stress disorder 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 neurotypicals, PTSD, and major depressive disorder cases across six regions implicated in the fear circuitry of the brain. We performed RNA-seq to examine changes in gene expression and link 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 brain.
RESULTS: We found significant differential methylation for PTSD near 195 genes and to further resolve the changes we observe, we constructed a cell type-specific DNA methylation 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 PTSD patients who responded to ketamine. Finally, to better understand the unique biology of PTSD, we analyzed matching methylation data for a cohort of MDD donors 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.
