Functional annotation of the human PTSD methylome identifies tissue-specific epigenetic variation across subcortical brain regions

Abstract

ABSTRACTPost-traumatic stress disorder is a mental disorder that may occur in the aftermath of severe psychological trauma. We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypicals, PTSD, and major depressive disorder cases across six areas implicated in the fear circuitry of the brain. We found significant differential methylation for PTSD near 195 genes and utilizing cross-region modeling, identified 6,641 candidate genes. Approximately 26% of differentially methylated CpGs were present near risk loci for PTSD. To identify potential therapeutic intersections for PTSD, we found significant methylation changes in theMAD1L1, ELFN1, andWNT5Agenes in ketamine responders. 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. Our results implicate DNAm as an epigenetic mechanism underlying the molecular changes associated with the subcortical fear circuitry of the PTSD brain.