Faculty Bibliography

This article reports on a study aimed to elucidate the complex etiology of post-traumatic stress (PTS) in a longitudinal cohort of police officers, by applying rigorous computational causal discovery (CCD) methods with observational data. An existing observational data set was used, which comprised a sample of 207 police officers who were recruited upon entry to police academy training. Participants were evaluated on a comprehensive set of clinical, self-report, genetic, neuroendocrine and physiological measures at baseline during academy training and then were re-evaluated at 12 months after training was completed. A data-processing pipeline-the Protocol for Computational Causal Discovery in Psychiatry (PCCDP)-was applied to this data set to determine a causal model for PTS severity. A causal model of 146 variables and 345 bivariate relations was discovered. This model revealed 5 direct causes and 83 causal pathways (of four steps or less) to PTS at 12 months of police service. Direct causes included single-nucleotide polymorphisms (SNPs) for the Histidine Decarboxylase (HDC) and Mineralocorticoid Receptor (MR) genes, acoustic startle in the context of low perceived threat during training, peritraumatic distress to incident exposure during first year of service, and general symptom severity during training at 1 year of service. The application of CCD methods can determine variables and pathways related to the complex etiology of PTS in a cohort of police officers. This knowledge may inform new approaches to treatment and prevention of critical incident related PTS.

Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event¹. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD)^2-4. At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma⁵. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment^6-9 to mitigate subsequent psychopathology in high-risk populations^10,11. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.

BACKGROUND:Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. METHODS:Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. RESULTS:A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. CONCLUSIONS:These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

Background: That PTSD is a heterogeneous condition is supported by both the failure to identify objective physiological measurements applicable to all who meet criteria for the disorder, and divergent responses associated with PTSD treatments.
Method(s): This study attempted to capitalize on biological diversity observed following epigenome-wide analysis in a well-characterized male veteran Discovery cohort (N=166) consisting of 83 PTSD+ and 83 PTSD- participants, to identify biologically relevant PTSD subtypes (biotypes) that might further improve molecular diagnosis and personalized treatment. Initial analysis revealed associations between DNA methylation (DNAm) profiles and 34 clinical features from which two epigenetically distinct biotypes - G1 and G2 - were derived.
Result(s): The findings were validated by examining participants (N=59) at a 3-year follow-up. Two other independent, cross-sectional veteran cohorts (N=54, and N=38, respectively), and a longitudinal active duty cohort (N = 133) were also used for validation of the initial biotypes. Interestingly, the biological pathways associated with the biotypes appeared to be regulated in opposite directions in comparison to controls. The impact of biotype-specific signal were evaluated in published DNAm markers, including an independent multi-omics biomarker developed using the same veteran cohort. Finally, we demonstrated filtering biotype-specific signal from a prior marker would result in a high-performance marker (AUC of 0.85).
Conclusion(s): 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 treatment-matching and monitoring of clinical outcome. Supported By: This work was supported by funding from the U.S. Army Research Office, through award numbersW911NF-13-1-0376, W911NF-17-2-0086, W911NF-18-2-0056, by the Army Research Laboratory under grant number W911NF-17-1-0069, and from the U.S. Department of Defense under W81XWH-10-1-0021, W81XWH-09-2-0044, and W81XWH-14-1-0043. Keywords: Biotypes, Epigenetic Biomarkers, Subtype Diagnosis, DNA Methylation, PT

Background/UNASSIGNED:United Nations (UN) personnel address a diverse range of political, social, and cultural crises throughout the world. Compared with other occupations routinely exposed to traumatic stress, there remains a paucity of research on mental health disorders and access to mental healthcare in this population. To fill this gap, personnel from UN agencies were surveyed for mental health disorders and mental healthcare utilization. Methods/UNASSIGNED:= 17 363) from 11 UN entities completed online measures of generalized anxiety disorder (GAD), major depressive disorder (MDD), posttraumatic stress disorder (PTSD), trauma exposure, mental healthcare usage, and socio-demographic information. Results/UNASSIGNED:Exposure to one or more traumatic events was reported by 36.2% of survey responders. Additionally, 17.9% screened positive for GAD, 22.8% for MDD, and 19.9% for PTSD. Employing multivariable logistic regressions, low job satisfaction, younger age (<35 years of age), greater length of employment, and trauma exposure on or off-duty was significantly associated with all the three disorders. Among individuals screening positive for a mental health disorder, 2.05% sought mental health treatment within and 10.01% outside the UN in the past year. Conclusions/UNASSIGNED:UN personnel appear to be at high risk for trauma exposure and screening positive for a mental health disorder, yet a small percentage screening positive for mental health disorders sought treatment. Despite the mental health gaps observed in this study, additional research is needed, as these data reflect a large sample of convenience and it cannot be determined if the findings are representative of the UN.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h²_snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h²_snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10^-8, FOXP1; rs10262462, p = 3.24 × 10^-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h²_snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r²â€‰= 0.0025; p = 1.8 × 10^-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r_g = 0.70, p = 4.65 × 10^-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

INTRODUCTION/BACKGROUND:Current pharmacological treatments of post-traumatic stress disorder (PTSD) have limited efficacy. Although the diagnosis is based on psychopathological criteria, it is frequently accompanied by somatic comorbidities and perhaps "accelerated biological aging," suggesting widespread physical concomitants. Such physiological comorbidities may affect core PTSD symptoms but are rarely the focus of therapeutic trials. METHODS:To elucidate the potential involvement of metabolism, inflammation, and mitochondrial function in PTSD, we integrate findings and mechanistic models from the DOD-sponsored "Systems Biology of PTSD Study" with previous data on these topics. RESULTS:Data implicate inter-linked dysregulations in metabolism, inflammation, mitochondrial function, and perhaps the gut microbiome in PTSD. Several inadequately tested targets of pharmacological intervention are proposed, including insulin sensitizers, lipid regulators, anti-inflammatories, and mitochondrial biogenesis modulators. CONCLUSIONS:Systemic pathologies that are intricately involved in brain functioning and behavior may not only contribute to somatic comorbidities in PTSD, but may represent novel targets for treating core psychiatric symptoms.