Faculty Bibliography
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Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: a meta-analysis of 23 military and civilian cohorts
BACKGROUND:The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. METHODS:As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using Illumina HumanMethylation450 or MethylationEPIC (850 K) BeadChips. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. RESULTS:We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e - 09 < p < 5.30e - 08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Out of 9 CpGs annotated to a gene expressed in blood, methylation levels at 5 CpGs showed significant correlations with the expression levels of their respective annotated genes. CONCLUSIONS:This study identifies 11 PTSD-associated CpGs and leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.
PMCID:11658418
PMID: 39696436
ISSN: 1756-994x
CID: 5764612
Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts
BACKGROUND:Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. METHODS:Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. RESULTS:The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. CONCLUSION/CONCLUSIONS:The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts.
PMID: 39334086
ISSN: 1755-8794
CID: 5706782
Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts
BACKGROUND/UNASSIGNED:The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. METHODS/UNASSIGNED:As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. RESULTS/UNASSIGNED:. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. CONCLUSIONS/UNASSIGNED:This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.
PMCID:11275670
PMID: 39072012
CID: 5731292
Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder
Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
PMID: 38637617
ISSN: 1546-1718
CID: 5655872
Treatment of Posttraumatic Stress Disorder: a State-of-the-art Review
This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of treatment yields a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.
PMID: 37132142
ISSN: 1875-6190
CID: 5544852
Trauma care in crisis: war trauma and mental health funding [Letter]
PMCID:11238647
PMID: 38984725
ISSN: 2000-8066
CID: 5698932
Get a Grip on Stress with Grippy! A Field Study to Understand Human-Wearable Partnerships in Stress Management
Smart wearables are increasingly used to help people deal with stress. Still, a less explored area of research in this field concerns the partnerships that smart wearables can take on when engaging people in stress-coping activities. To facilitate further understanding of the human-wearable partnerships, we designed Grippy, a smart wearable system composed of a physical glove and a smartphone application to help the wearer actively explore and cope with stress in daily situations. We introduced Grippy, as a speculative probe, to six participants (four master students and two university employees) who wore it for five successive days. Participants were interviewed about their use experience of Grippy during and after these five days. Qualitative data collected from the interviews was interpreted regarding how Grippy could fit into people"™s stress-coping activities across different daily contexts and what kinds of partnerships with the smart wearable were perceived by the participants. In addition, we reflect on the design issues that led to the mismatch between our design intentions and people"™s actual use experiences. We discuss how these results have deepened our understanding of human-wearable partnerships in the context of stress management and the usability issues that might hinder the expression and acceptance of smart wearables designed as partners. We end the discussion by reflecting on the implications of smart wearables as partners in mental healthcare.
SCOPUS:85146157235
ISSN: 1991-3761
CID: 5408562
Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information
BACKGROUND:Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS:A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (NÂ = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (NÂ = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS:GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS:Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
PMID: 34865855
ISSN: 1873-2402
CID: 5079282
Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
PMID: 34992238
ISSN: 1476-5578
CID: 5136862
Successful treatment of post-traumatic stress disorder reverses DNA methylation marks
Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = -0.84, t = -2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.
PMID: 31645664
ISSN: 1476-5578
CID: 4175692
