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.

The time course of feature-selective attention inside and outside the focus of spatial attention.

Research on attentional selection of stimulus features has yielded seemingly contradictory results. On the one hand, many experiments in humans and animals have observed a "global" facilitation of attended features across the entire visual field, even when spatial attention is focused on a single location. On the other hand, several event-related potential studies in humans reported that attended features are enhanced at the attended location only. The present experiment demonstrates that these conflicting results can be explained by differences in the timing of attentional allocation inside and outside the spatial focus of attention. Participants attended to fields of either red or blue randomly moving dots on either the left or right side of fixation with the task of detecting brief coherent motion targets. Recordings of steady-state visual evoked potentials elicited by the flickering stimuli allowed concurrent measurement of the time course of feature-selective attention in visual cortex on both the attended and the unattended sides. The onset of feature-selective attentional modulation on the attended side occurred around 150 ms earlier than on the unattended side. This finding that feature-selective attention is not spatially global from the outset but extends to unattended locations after a temporal delay resolves previous contradictions between studies finding global versus hierarchical selection of features and provides insight into the fundamental relationship between feature-based and location-based (spatial) attention mechanisms.

Protocol for generating customizable and reproducible plots of sequencing coverage data using the seqNdisplayR package.

The widespread usage of next-generation sequencing methods for functional genomics studies requires standardized tools for consistent visualization of the associated data. Here, we present seqNdisplayR, an R package for plotting standard sequencing data coverage within a genomic region of interest in a customizable and reproducible manner. We describe steps for installing software, preparing data files, choosing options, and plotting data. This tool is readily available for users with no prior experience with R through the "Shiny app" interface. For complete details on the use and execution of this protocol, please refer to Lykke-Andersen et al.,1 Gockert et al.,2 and Rouviere et al.3.

Mental healthcare utilisation among Danish formerly deployed military personnel and their civilian counterparts: a cohort study.

Background: Prior studies comparing the mental healthcare utilisation (MHU) of Danish formerly deployed military personnel (FDP) with the general population have not included data on psychotherapy through the Defence or talking therapy with the general practitioner. This study included these and several other data sources in a comprehensive comparison of MHU between Danish FDP and civilians.Methods: First-time deployed military personnel (N = 10,971) who had returned from a mission to Kosovo, Afghanistan, Iraq or Lebanon between January 2005 and July 2017 were included. A sex and birth-year-matched civilian reference group was randomly drawn from the entire Danish non-deployed population (N = 253,714). Furthermore, a sub-cohort, including male FDP and civilians deemed eligible for military service, was defined. These cohorts were followed up in military medical records and registers covering the primary and secondary civilian health sectors from 2005 to 2018, and the rates of MHU were compared.Results: Approximately half of the initial help-seeking for FDP took place through the Defence (49.4%), and the remainder through the civilian healthcare system. When help-seeking through the Defence was not included, MHU was significantly lower among FDP in the main cohort during the first two years (IRR = 0.84, 95% CI: [0.77, 0.92]) compared to civilians. When help-seeking through the Defence was included, MHU was significantly higher among FDP compared to civilians both in the first two years of follow-up (IRR = 2.01, 95% CI: [1.89, 2.13]) and thereafter (IRR = 1.18, 95% CI: [1.13, 1.23]). In the sub-cohort, these differences were even more pronounced both in the first two years of follow-up and thereafter.Conclusions: MHU was higher among Danish FDP compared to civilians only when data from the Defence was included. The inclusion of data on both civilian and military healthcare services is necessary to evaluate the full impact of deployment on MHU among Danish FDP.

This study compared mental healthcare utilisation among Danish deployed military personnel and civilians.Most personnel sought help first through the Defence.When all data sources were included, mental healthcare utilisation was significantly higher among military personnel.

Attentional Modulation in Early Visual Cortex: A Focused Reanalysis of Steady-state Visual Evoked Potential Studies.

Steady-state visual evoked potentials (SSVEPs) are a powerful tool for investigating selective attention. Here, we conducted a combined reanalysis of multiple studies employing this technique in a variety of attentional experiments to, first, establish benchmark effect sizes of attention on amplitude and phase of SSVEPs and, second, harness the power of a large data set to test more specific hypotheses. Data of eight published SSVEP studies were combined, in which human participants (n = 135 in total) attended to flickering random dot stimuli based on their defining features (e.g., location, color, luminance, or orientation) or feature conjunctions. The reanalysis established that, in all the studies, attention reliably enhanced amplitudes, with color-based attention providing the strongest effect. In addition, the latency of SSVEPs elicited by attended stimuli was reduced by ∼4 msec. Next, we investigated the modulation of SSVEP amplitudes in a subset of studies where two different features were attended concurrently. Although most models assume that attentional effects of multiple features are combined additively, our results suggest that neuronal enhancement provided by concurrent attention is better described by multiplicative integration. Finally, we used the combined data set to demonstrate that the increase in trial-averaged SSVEP amplitudes with attention cannot be explained by increased synchronization of single-trial phases. Contrary to the prediction of the phase-locking account, the variance across trials of complex Fourier coefficients increases with attention, which is more consistent with boosting of a largely phase-locked signal embedded in non-phase-locked noise.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic 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 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, 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.

Feasibility of Virtual Reality Exposure Therapy in the Treatment of Danish Veterans with Post-Traumatic Stress Disorder: A Mixed Method Pilot Study.

The BraveMind virtual reality exposure therapy (VRET) has been developed and has shown efficacy for U.S. service members and veterans. As the first study to date, the present study examined the feasibility of BraveMind VRET for non-U.S. military veterans. Moreover, the study sought to explore in-depth the participants' experiences with BraveMind VRET. Nine Danish veterans with post-traumatic stress disorder (PTSD) after deployment to Afghanistan participated in the study. PTSD, depression, and quality of life were assessed at pretreatment, post-treatment, and 3-month followup. The treatment consisted of 10 BraveMind VRET sessions. Semistructured interviews with treatment completers were conducted post-treatment to ascertain views about the treatment, in general, and the BraveMind VR system in particular. Thematic qualitative analysis was conducted at the semantic level using an inductive approach. There were significant reductions in pre- to post-treatment self-reported PTSD and significant improvements in quality of life. Treatment gains were maintained at 3-month followup. Pre- to post-treatment Cohen's d effect sizes were large for self-reported PTSD (PTSD Checklist-Civilian Version [PCL-C]: d = 1.55). Qualitative results indicated that the virtual environment of the BraveMind VR system does not entirely map the reality of Danish soldiers in Afghanistan. However, this was not experienced as a hindering factor in therapy. Findings indicate that BraveMind VRET is an acceptable, safe, and effective treatment for Danish veterans with PTSD. The qualitative results emphasize the importance of a strong therapeutic alliance, as VRET is experienced as more emotional straining than regular trauma-focused therapy.

ARS2 instructs early transcription termination-coupled RNA decay by recruiting ZC3H4 to nascent transcripts.

The RNA-binding ARS2 protein is centrally involved in both early RNA polymerase II (RNAPII) transcription termination and transcript decay. Despite its essential nature, the mechanisms by which ARS2 enacts these functions have remained unclear. Here, we show that a conserved basic domain of ARS2 binds a corresponding acidic-rich, short linear motif (SLiM) in the transcription restriction factor ZC3H4. This interaction recruits ZC3H4 to chromatin to elicit RNAPII termination, independent of other early termination pathways defined by the cleavage and polyadenylation (CPA) and Integrator (INT) complexes. We find that ZC3H4, in turn, forms a direct connection to the nuclear exosome targeting (NEXT) complex, hereby facilitating rapid degradation of the nascent RNA. Hence, ARS2 instructs the coupled transcription termination and degradation of the transcript onto which it is bound. This contrasts with ARS2 function at CPA-instructed termination sites where the protein exclusively partakes in RNA suppression via post-transcriptional decay.

Risk factors, comorbidity and social impairment of ICD-11 PTSD and complex PTSD in Danish treatment-seeking military veterans.

PURPOSE: While a number of studies have investigated risk factors and comorbidities of ICD-11 post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD) in various trauma exposed samples, few studies have been conducted in military samples. Existing studies with military samples have included rather small samples. The aim of the present study was to identify risk factors and comorbidities of ICD-11 PTSD and CPTSD in a large sample of previously deployed, treatment-seeking soldiers and veterans. METHODS: Previously deployed, treatment-seeking Danish soldiers and veterans (N = 599), recruited from the Military Psychology Department of the Danish Defense, completed the International Trauma Questionnaire (ITQ), as well as questionnaires of common mental health difficulties, trauma exposure, functioning and demographics. Multivariate multinomial logistic regression analysis explored differences in self-reported exposure to adversity and health outcomes between those meeting ICD-11 criteria for probable PTSD, CPTSD and no trauma disorder. RESULTS: A total of 13.0% met probable ICD-11 criteria for PTSD and 31.4% for CPTSD. Risk factors for CPTSD (compared to those with no trauma disorder) included exposure to warfare or combat, longer duration since the traumatic event and being single. Those with CPTSD were more likely than those with PTSD or no trauma disorder to endorse symptoms of depression, anxiety, stress, use of psychotropic medication, and suicide attempts. CONCLUSION: CPTSD is a more common and debilitating condition compared to PTSD in treatment-seeking soldiers and veterans. Further research should focus on testing existing and novel interventions for CPTSD in the military.

Early prediction of mental health problems following military deployment: Integrating pre- and post-deployment factors in neural network models.

Military personnel deployed to war zones are at increased risk of mental health problems such as posttraumatic stress disorder (PTSD) or depression. Early pre- or post-deployment identification of those at highest risk of such problems is crucial to target intervention to those in need. However, sufficiently accurate models predicting objectively assessed mental health outcomes have not been put forward. In a sample consisting of all Danish military personnel who deployed to war zones for the first (N = 27,594), second (N = 11,083) and third (N = 5,161) time between 1992 and 2013, we apply neural networks to predict psychiatric diagnoses or use of psychotropic medicine in the years following deployment. Models are based on pre-deployment registry data alone or on pre-deployment registry data in combination with post-deployment questionnaire data on deployment experiences or early post-deployment reactions. Further, we identified the most central predictors of importance for the first, second, and third deployment. Models based on pre-deployment registry data alone had lower accuracy (AUCs ranging from 0.61 (third deployment) to 0.67 (first deployment)) than models including pre- and post-deployment data (AUCs ranging from 0.70 (third deployment) to 0.74 (first deployment)). Age at deployment, deployment year and previous physical trauma were important across deployments. Post-deployment predictors varied across deployments but included deployment exposures as well as early post-deployment symptoms. The results suggest that neural network models combining pre- and early post-deployment data can be utilized for screening tools that identify individuals at risk of severe mental health problems in the years following military deployment.

Attentional modulation as a mechanism for enhanced facial emotion discrimination: The case of action video game players.

Action video game players (AVGPs) outperform nonvideo game players (NVGPs) on a wide variety of attentional tasks, mediating benefits to perceptual and cognitive decision processes. A key issue in the literature is the extent to which such benefits transfer beyond cognition. Using steady-state visual evoked potentials (SSVEP) as a neural measure of attentional resource allocation, we investigated whether the attentional benefit of AVGPs generalizes to the processing of rapidly presented facial emotions. AVGPs (n = 36) and NVGPs (n = 32) performed a novel, attention-demanding emotion discrimination task, requiring the identification of a target emotion in one of two laterally presented streams of emotional faces. The emotional faces flickered at either 2.0 Hz or 2.5 Hz. AVGPs outperformed NVGPs at detecting the target emotions regardless of the type of emotion. Correspondingly, attentional modulation of the SSVEP at parieto-occipital recording sites was larger in AVGPs compared with NVGPs. This difference appeared to be driven by a larger response to attended information, as opposed to a reduced response to irrelevant distractor information. Exploratory analyses confirmed that this novel paradigm elicited the expected pattern of event-related potentials associated with target detection and error processing. These components did not, however, differ between groups. Overall, the results indicate enhanced discrimination of facial emotions in AVGPs arising from enhanced attentional processing of emotional information. This presents evidence for the attentional advantage of AVGPs to extend beyond perceptual and cognitive processes.

Attentional Enhancement of Tracked Stimuli in Early Visual Cortex Has Limited Capacity.

Keeping track of the location of multiple moving objects is one of the well documented functions of visual attention. However, the mechanism of attentional selection that supports such continuous tracking is unclear. In particular, it has been proposed that target selection in early visual cortex occurs in parallel, with tracking errors arising because of attentional limitations at later processing stages. Here, we examine whether, instead, total attentional capacity for enhancement of early visual processing of tracked targets is shared between all attended stimuli. If the magnitude of attentional facilitation of multiple tracked targets was a key limiting factor of tracking ability, then one should expect it to drop systematically with increasing set-size of tracked targets. Human observers (male and female) were instructed to track two, four, or six moving objects among a pool of identical distractors. Steady-state visual evoked potentials (SSVEPs) recorded during the tracking period revealed that the processing of tracked targets was consistently amplified compared with the processing of the distractors. The magnitude of this amplification decreased with increasing set size, and at lateral occipital electrodes it closely followed inverse proportionality to the number of tracked items, suggesting that limited attentional resources must be shared among the tracked stimuli. Accordingly, the magnitude of attentional facilitation predicted the behavioral outcome at the end of the trial. Together, these findings demonstrate that the limitations of multiple object tracking (MOT) across set-sizes stem from the limitations of top-down selective attention already at the early stages of visual processing.SIGNIFICANCE STATEMENT The ability to selectively attend to relevant features or objects is the key to flexibility of perception and action in the continuously changing environment. This ability is demonstrated in the multiple object tracking (MOT) task where observers monitor multiple independently moving objects at different locations in the visual field. The role of early attentional enhancement in tracking was previously acknowledged in the literature, however, the limitations on tracking were thought to arise during later stages of processing. Here, we demonstrate that the strength of attentional facilitation depends on the number of tracked objects and predicts successful tracking performance. Thus, it is the limitations of attentional enhancement at the early stages of visual processing that determine behavioral performance limits.

Resting-state EEG functional connectivity predicts post-traumatic stress disorder subtypes in veterans.

Objective. Post-traumatic stress disorder (PTSD) is highly heterogeneous, and identification of quantifiable biomarkers that could pave the way for targeted treatment remains a challenge. Most previous electroencephalography (EEG) studies on PTSD have been limited to specific handpicked features, and their findings have been highly variable and inconsistent. Therefore, to disentangle the role of promising EEG biomarkers, we developed a machine learning framework to investigate a wide range of commonly used EEG biomarkers in order to identify which features or combinations of features are capable of characterizing PTSD and potential subtypes.Approach. We recorded 5 min of eyes-closed and 5 min of eyes-open resting-state EEG from 202 combat-exposed veterans (53% with probable PTSD and 47% combat-exposed controls). Multiple spectral, temporal, and connectivity features were computed and logistic regression, random forest, and support vector machines with feature selection methods were employed to classify PTSD. To obtain robust results, we performed repeated two-layer cross-validation to test on an entirely unseen test set.Main results. Our classifiers obtained a balanced test accuracy of up to 62.9% for predicting PTSD patients. In addition, we identified two subtypes within PTSD: one where EEG patterns were similar to those of the combat-exposed controls, and another that were characterized by increased global functional connectivity. Our classifier obtained a balanced test accuracy of 79.4% when classifying this PTSD subtype from controls, a clear improvement compared to predicting the whole PTSD group. Interestingly, alpha connectivity in the dorsal and ventral attention network was particularly important for the prediction, and these connections were positively correlated with arousal symptom scores, a central symptom cluster of PTSD.Significance. Taken together, the novel framework presented here demonstrates how unsupervised subtyping can delineate heterogeneity and improve machine learning prediction of PTSD, and may pave the way for better identification of quantifiable biomarkers.

Applying historical data in a nonlinear mixed-effects model can reduce the number of control rats required for calculation of the relative potency of insulin analogues.

This paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A dataset consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a mixed-effect meta-analysis approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats.

Adverse Events and All-Cause Mortality in Danish Patients with Cerebral Venous Thrombosis: A Nationwide Cohort Study.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare manifestation of stroke and venous thromboembolism (VTE), compared with deep vein thrombosis (DVT) and pulmonary embolism (PE). We examined whether CVT was associated with adverse cardiovascular events. METHODS: A Danish cohort study with adult patients diagnosed with CVT (N = 1,015) between 1997 and 2017. We matched 10 patients with VTE (DVT and PE) to each patient with CVT for age, sex, and diagnosis year. We also matched 10 individuals from the general population to each patient with CVT. We computed cumulative incidence and estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs) at 5 years for major bleeding, intracranial bleeding, ischemic stroke, and cardiovascular events. Death was examined separately. RESULTS: Major bleeding risks were 1.2% for CVT and 0.7% for VTE at 6 months; these risks increased to 2.7% and 2.6%, respectively, at 5 years. Although rare, intracranial bleeding risks were markedly higher for CVT (2.9%) than for VTE (0.4%) at 5 years (HR = 8.9, 95% CI: 5.3-15.1). Incidences of ischemic stroke were 5.9% for CVT and 0.3% for VTE, at 6 months; and 10.0% and 1.4%, respectively, at 5 years (HR = 9.5, 95% CI: 7.1-12.7). In contrast, incidence of cardiac events was lower for CVT that VTE (1.7% vs. 3.6% at 5 years). Mortality risk was higher after CVT compared with VTE, at 6 months (6.6% vs. 3.8%), but the risks differed little at 5 years (14.3% vs. 14.1%). CONCLUSION: Intracranial bleeding, ischemic stroke, and mortality risks were higher for patients with CVT than matched patients with VTE and the general population, particularly within 6 months after diagnosis.

Phasic Alertness and Multisensory Integration Contribute to Visual Awareness of Weak Visual Targets in Audio-Visual Stimulation under Continuous Flash Suppression.

Multisensory stimulation is associated with behavioural benefits, including faster processing speed, higher detection accuracy, and increased subjective awareness. These effects are most likely explained by multisensory integration, alertness, or a combination of the two. To examine changes in subjective awareness under multisensory stimulation, we conducted three experiments in which we used Continuous Flash Suppression to mask subthreshold visual targets for healthy observers. Using the Perceptual Awareness Scale, participants reported their level of awareness of the visual target on a trial-by-trial basis. The first experiment had an audio-visual Redundant Signal Effect paradigm, in which we found faster reaction times in the audio-visual condition compared to responses to auditory or visual signals alone. In two following experiments, we separated the auditory and visual signals, first spatially (experiment 2) and then temporally (experiment 3), to test whether the behavioural benefits in our multisensory stimulation paradigm could best be explained by multisensory integration or increased phasic alerting. Based on the findings, we conclude that the largest contributing factor to increased awareness of visual stimuli accompanied by auditory tones is a rise in phasic alertness and a reduction in temporal uncertainty with a small but significant contribution of multisensory integration.

Ten simple rules to study distractor suppression.

Distractor suppression refers to the ability to filter out distracting and task-irrelevant information. Distractor suppression is essential for survival and considered a key aspect of selective attention. Despite the recent and rapidly evolving literature on distractor suppression, we still know little about how the brain suppresses distracting information. What limits progress is that we lack mutually agreed upon principles of how to study the neural basis of distractor suppression and its manifestation in behavior. Here, we offer ten simple rules that we believe are fundamental when investigating distractor suppression. We provide guidelines on how to design conclusive experiments on distractor suppression (Rules 1-3), discuss different types of distractor suppression that need to be distinguished (Rules 4-6), and provide an overview of models of distractor suppression and considerations of how to evaluate distractor suppression statistically (Rules 7-10). Together, these rules provide a concise and comprehensive synopsis of promising advances in the field of distractor suppression. Following these rules will propel research on distractor suppression in important ways, not only by highlighting prominent issues to both new and more advanced researchers in the field, but also by facilitating communication between sub-disciplines.

Control of non-productive RNA polymerase II transcription via its early termination in metazoans.

Transcription establishes the universal first step of gene expression where RNA is produced by a DNA-dependent RNA polymerase. The most versatile of eukaryotic RNA polymerases, RNA polymerase II (Pol II), transcribes a broad range of DNA including protein-coding and a variety of non-coding transcription units. Although Pol II can be configured as a durable enzyme capable of transcribing hundreds of kilobases, there is reliable evidence of widespread abortive Pol II transcription termination shortly after initiation, which is often followed by rapid degradation of the associated RNA. The molecular details underlying this phenomenon are still vague but likely reflect the action of quality control mechanisms on the early Pol II complex. Here, we summarize current knowledge of how and when such promoter-proximal quality control is asserted on metazoan Pol II.

Changes in perceived social support and PTSD symptomatology among Danish army military personnel.

PURPOSE: Previous research has identified social support to be associated with risk of posttraumatic stress disorder (PTSD) symptoms among military personnel. While the lack of social support influences PTSD symptomatology, it is unknown how changes in perceived social support affect the PTSD symptom level in the aftermath of deployment. Furthermore, the influence of specific sources of social support from pre- to post-deployment on level of PTSD symptoms is unknown. We aim to examine how changes in perceived social support (overall and from specific sources) from pre- to 2.5 year post-deployment are associated with the level of post-deployment PTSD symptoms. METHODS: Danish army military personnel deployed to Afghanistan in 2009 and 2013 completed questionnaires at pre-deployment and at 2.5 year post-deployment measuring perceived social support and PTSD symptomatology and sample characteristics of the two cohorts. Data were analyzed using univariate and multivariate nominal logistic regression. RESULTS: Negative changes in perceived social support from pre- to post-deployment were associated with both moderate (OR 1.99, CI 1.51-2.57) and high levels (OR 2.71, CI 1.94-3.78) of PTSD symptoms 2.5 year post-deployment (adjusted analysis). Broadly, the same direction was found for specific sources of social support and level of PTSD symptoms. In the adjusted analyses, pre-deployment perceived social support and military rank moderated the associations. CONCLUSIONS: Deterioration in perceived social support (overall and specific sources) from pre- to 2.5 year post-deployment increases the risk of an elevated level of PTSD symptoms 2.5 year post-deployment.

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 (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.