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... Show moreBACKGROUND: 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 (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 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. Show less
Background In recent years, a new framework for analyzing and understanding posttraumatic stress disorder (PTSD) was introduced; the network approach. Up until now, network analysis studies of PTSD... Show moreBackground In recent years, a new framework for analyzing and understanding posttraumatic stress disorder (PTSD) was introduced; the network approach. Up until now, network analysis studies of PTSD were largely conducted on small to medium sample sizes (N < 1,000), which might be a possible cause of variability in main findings. Moreover, only a limited number of network studies investigated comorbidity.Methods In this study, we utilized a large sample to conduct a network analysis of 17 symptoms of PTSD (DSM-IV), and compared it to the result of a second network consisting of symptoms of PTSD and depression (based on Patient Health Questionnaire-9 [PHQ-9]). Our sample consisted of 502,036 treatment-seeking veterans, out of which 158,139 had fully completed the assessment of symptoms of PTSD and a subsample of 32,841 with valid PCL and PHQ-9 that was administered within 14 days or less.Results Analyses found that in the PTSD network, the most central symptoms were feeling distant or cut off from others, followed by feeling very upset when reminded of the event, and repeated disturbing memories or thoughts of the event. In the combined network, we found that concentration difficulties and anhedonia are two of the five most central symptoms.Conclusion Our findings replicate the centrality of intrusion symptoms in PTSD symptoms' network. Taking into account the large sample and high stability of the network structure, we believe our study can answer some of the criticism regarding stability of cross-sectional network structures. Show less
The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and... Show moreThe risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations. Show less
Von Stockert, S.H.H.; Fried, E.I.; Armour, C.; Pietrzak, R.H. 2017
Background Previous studies have used network models to investigate how PTSD symptoms associate with each other. However, analyses examining the degree to which these networks are stable over time... Show moreBackground Previous studies have used network models to investigate how PTSD symptoms associate with each other. However, analyses examining the degree to which these networks are stable over time, which are critical to identifying symptoms that may contribute to the chronicity of this disorder, are scarce. In the current study, we evaluated the temporal stability of DSM-5 PTSD symptom networks over a three-year period in a nationally representative sample of trauma-exposed U.S. military veterans. Methods Data were analyzed from 611 trauma-exposed U.S. military veterans who participated in the National Health and Resilience in Veterans Study (NHRVS). We estimated regularized partial correlation networks of DSM-5 PTSD symptoms at baseline (Time 1) and at three-year follow-up (Time 2), and examined their temporal stability. Results Evaluation of the network structure of PTSD symptoms at Time 1 and Time 2 using a formal network comparison indicated that the Time 1 network did not differ significantly from the Time 2 network with regard to network structure (p = 0.12) or global strength (sum of all absolute associations, i.e. connectivity; p = 0.25). Centrality estimates of both networks (r = 0.86) and adjacency matrices (r = 0.69) were highly correlated. In both networks, avoidance, intrusive, and negative cognition and mood symptoms were among the more central nodes. Limitations This study is limited by the use of a self-report instrument to assess PTSD symptoms and recruitment of a relatively homogeneous sample of predominantly older, Caucasian veterans. Conclusion Results of this study demonstrate the three-year stability of DSM-5 PTSD symptom network structure in a nationally representative sample of trauma-exposed U.S. military veterans. They further suggest that trauma-related avoidance, intrusive, and dysphoric symptoms may contribute to the chronicity of PTSD symptoms in this population. Show less
