Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males

Ruoting Yang,Kelsey R Dean,Rachel Yehuda,Francis J Doyle,Charles R Marmar,Kerry J Ressler,Duna Abu‐Amara ,Stacy Ann Miller ,Inyoul Lee,Janine D Flory,Seid Muhie,Burook Misganaw,Synthia H Mellon,Leroy Hood,Bernie J Daigle,Owen M Wolkowitz,Aarti Gautam,Rasha Hammamieh,Raina Kumar,Kai Wang,Derese Getnet,Marti Jett

doi:10.1038/s41380-020-00966-2

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.

Highlights

Post-traumatic stress disorder (PTSD) is a stress-related syndrome that develops in many following exposure to a myriad of biological differences has been noted between groups of trauma survivors with or without PTSD, a bona fide diagnostic test for this disorder that provides high sensitivity and specificity has been elusive
The approach used for subtype detection is based on identifying different biological correlates associated with symptoms that seemed to be present in only a subset of individuals with PTSD
Lanius et al estimated that the PTSD patient population could be divided into 70% with a re-experiencing/hyperarousal subtype and 30% with a dissociative subtype [7], and these subtypes showed distinct activations in the medial prefrontal brain regions using functional magnetic resonance imaging [8, 9]

Summary

Introduction

Post-traumatic stress disorder (PTSD) is a stress-related syndrome that develops in many following exposure to a myriad of biological differences has been noted between groups of trauma survivors with or without PTSD, a bona fide diagnostic test for this disorder that provides high sensitivity and specificity has been elusive. One of the major barriers to identifying PTSD biomarkers is that as more symptoms are added to the diagnosis, the number of different PTSD presentations is increased, resulting in a remarkably heterogeneous disorder. There have been efforts to symptomatically classify PTSD into distinct pathological post-traumatic phenotypes, resulting in an official dissociative subtype in the DSM-5 [5, 6]. The approach used for subtype detection is based on identifying different biological correlates associated with symptoms that seemed to be present in only a subset of individuals with PTSD. Drysdale et al identified ‘biotypes’ from objective biological measurements (fMRI in this case), and the biotypes associated with the clinical/symptomatic correlates [11, 12]. The biotypes stratified the biological variation resulting in different clinical phenotypes and hereby inferred more targeted/personalized objective markers and treatment. The current study attempted to identify PTSD biotypes using blood epigenome-wide array data

Methods

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Discussion

Conclusion