Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males
Ruoting Yang, Aarti Gautam, Derese Getnet, Bernie J. Daigle, Stacy Ann Miller, Burook Misganaw, Kelsey R. Dean, Raina Kumar, Seid Muhie, Kai Wang, Inyoul Lee, Duna Abu‐Amara, Janine D. Flory, Allison Hoke, Nabarun Chakraborty, Linda Petzold, Gwyneth W. Y. Wu, Guia Guffanti, Taek‐Kyun Kim, Min Young Lee, Linda M. Bierer, Leroy Hood, Owen M. Wolkowitz, Synthia H. Mellon, Francis J. Doyle, Rachel Yehuda, Charles R. Marmar, Kerry J. Ressler, Rasha Hammamieh, Marti Jett
Abstract
Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.