Application of an egocentric social network approach to examine changes in social connections following treatment for anxiety and depression: A novel measurement tool for clinical trials research?

The epidemic of loneliness and social isolation has been recognized as a public health crisis warranting the same prioritization as other public health issues today, such as obesity, substance use disorders, and tobacco use. Social disconnection is particularly prevalent and disabling among individuals with anxiety and depression, yet it is inadequately evaluated and addressed in most clinical psychology treatment research. Studies generally employ global measures of perceived connectedness, loneliness, or relationship satisfaction, limiting understanding about elements of one's social network that may change with treatment. This study examined changes in the degree (number of people nominated) and quality of one's social network from pre-to post-treatment using an egocentric social network approach in 59 adults (mean age = 30.8 years, range = 18 to 54) with clinically elevated anxiety or depression who were randomized to a cognitive and behavioral positive valence treatment versus waitlist. Participants (egos) named people in their lives (alters) with whom they discussed important issues or spent free time. For each alter, participants rated how close they felt, how close they thought the alter felt to them, and how frequently they communicated. Linear regressions, which included treatment group as a predictor, revealed no group differences in changes in network degree, perceived alter feelings of closeness, or communication frequency, despite prior findings from this sample indicating larger increases in perceived global connectedness in the treatment group. Unexpectedly, the control group reported a greater increase in perceived closeness to alters. Post-hoc analyses revealed this was explained by the treatment group identifying more distal social ties (e.g., extended family, colleagues, roommates) as alters following treatment - an outcome positively associated with global improvements in connectedness. This proof-of-concept study suggests egocentric social network surveys may provide unique information on treatment-related changes in social functioning. Suggestions are provided for adaptations to facilitate application of social network surveys to mental health treatment research.

PTSD, Comorbidities, Gender, and Increased Risk of Cardiovascular Disease in a Large Military Cohort.

Importance: Posttraumatic stress disorder (PTSD) is a prevalent mental health problem that increases risk of cardiovascular disease (CVD). It is not known whether gender or comorbidities modify associations between PTSD and CVD. Objective: To assess risk of hypertension and atherosclerotic CVD (ASCVD) associated with PTSD in a predominantly young military population, and determine if gender or PTSD comorbidities modify these associations. Design setting and participants: Using administrative medical records, this longitudinal, retrospective cohort study assessed relationships of PTSD, gender, comorbidities (metabolic risk factors [MRF], behavioral risk factors [BRF], depression, and sleep disorders) to subsequent hypertension and ASCVD among 863,993 active-duty U.S. Army enlisted soldiers (86.2% male; 93.7%

Genetic influences and causal pathways shared between cannabis use disorder and other substance use traits.

Cannabis use disorder (CanUD) has increased with the legalization of the use of cannabis. Around 20% of individuals using cannabis develop CanUD, and the number of users has grown with increasing ease of access. CanUD and other substance use disorders (SUDs) are associated phenotypically and genetically. We leveraged new CanUD genomics data to undertake genetically-informed analyses with unprecedented power, to investigate the genetic architecture and causal relationships between CanUD and lifetime cannabis use with risk for developing SUDs and substance use traits. Analyses included calculating local and global genetic correlations, genomic structural equation modeling (genomicSEM), and Mendelian Randomization (MR). Results from the genetic correlation and genomicSEM analyses demonstrated that CanUD and cannabis use differ in their relationships with SUDs and substance use traits. We found significant causal effects of CanUD influencing all the analyzed traits: opioid use disorder (OUD) (Inverse variant weighted, IVW ß = 0.925 ± 0.082), problematic alcohol use (PAU) (IVW ß = 0.443 ± 0.030), drinks per week (DPW) (IVW ß = 0.182 ± 0.025), Fagerström Test for Nicotine Dependence (FTND) (IVW ß = 0.183 ± 0.052), cigarettes per day (IVW ß = 0.150 ± 0.045), current versus former smokers (IVW ß = 0.178 ± 0.052), and smoking initiation (IVW ß = 0.405 ± 0.042). We also found evidence of bidirectionality showing that OUD, PAU, smoking initiation, smoking cessation, and DPW all increase risk of developing CanUD. For cannabis use, bidirectional relationships were inferred with PAU, smoking initiation, and DPW; cannabis use was also associated with a higher risk of developing OUD (IVW ß = 0.785 ± 0.266). GenomicSEM confirmed that CanUD and cannabis use load onto different genetic factors. We conclude that CanUD and cannabis use can increase the risk of developing other SUDs. This has substantial public health implications; the move towards legalization of cannabis use may be expected to increase other kinds of problematic substance use. These harmful outcomes are in addition to the medical harms associated directly with CanUD.

Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10-18), CanUD (rg = 0.37, p = 8.21 × 10-37), OUD (rg = 0.20, p = 1.50 × 10-3), and PTU (rg = 0.29, p = 8.53 × 10-12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10-4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10-6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10-8; pain-outcome: beta = 0.09, p = 3.05 × 10-6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10-8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10-5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.

Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality.

Substance dependence diagnoses (SDs) are important risk factors for suicidality. We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (N = 15,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (N = 11,236) was recruited to evaluate mental health risk and resilience among Army personnel. We applied multivariate logistic regression to investigate the associations of SDs with suicidality and, in the Yale-Penn cohort, we used the structured linear mixed model (StructLMM) to study multivariate gene-environment interactions. In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidality: having five SDs showed an association with suicidality, from odds ratio (OR) = 6.77 (95% confidence interval, CI = 5.74-7.99) for suicidal ideation (SI) to OR = 3.61 (95% CI = 2.7-4.86) for suicide attempt (SA). In Army STARRS, having multiple substance use disorders for alcohol and/or drugs was associated with increased suicidality ranging from OR = 2.88 (95% CI = 2.6-3.19) for SI to OR = 3.92 (95% CI = 3.19-4.81) for SA. In Yale-Penn, we identified multivariate gene-environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p = 1.82 × 10-7; TSNAXIP1, p = 2.13 × 10-7; CENPT, p = 2.32 × 10-7; PARD6A, p = 5.57 × 10-7) for opioid dependence (BF = 12.2), cocaine dependence (BF = 12.1), nicotine dependence (BF = 9.2), and polysubstance dependence (BF = 2.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry.

Importance: Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished. Objective: To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits. Design, Setting, and Participants: A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020. Main Outcomes and Measures: Estimates of single nucleotide variation (SNV)-based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed. Results: Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (ß = 0.133; P = .003) and years of education had a protective effect (ß = -0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (ß = 0.072, P = .001 and ß = 1.546, P = <.001, respectively). Conclusions and Relevance: This large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disorder.

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

BACKGROUND: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10-7, padj = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10-6), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10-5, padj = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10-6, padj = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program.

OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

Developing an optimal short-form of the PTSD Checklist for DSM-5 (PCL-5).

BACKGROUND: Although several short-forms of the posttraumatic stress disorder (PTSD) Checklist (PCL) exist, all were developed using heuristic methods. This report presents the results of analyses designed to create an optimal short-form PCL for DSM-5 (PCL-5) using both machine learning and conventional scale development methods. METHODS: The short-form scales were developed using independent datasets collected by the Army Study to Assess Risk and Resilience among Service members. We began by using a training dataset (n = 8,917) to fit short-form scales with between 1 and 8 items using different statistical methods (exploratory factor analysis, stepwise logistic regression, and a new machine learning method to find an optimal integer-scored short-form scale) to predict dichotomous PTSD diagnoses determined using the full PCL-5. A smaller subset of best short-form scales was then evaluated in an independent validation sample (n = 11,728) to select one optimal short-form scale based on multiple operating characteristics (area under curve [AUC], calibration, sensitivity, specificity, net benefit). RESULTS: Inspection of AUCs in the training sample and replication in the validation sample led to a focus on 4-item integer-scored short-form scales selected with stepwise regression. Brier scores in the validation sample showed that a number of these scales had comparable calibration (0.015-0.032) and AUC (0.984-0.994), but that one had consistently highest net benefit across a plausible range of decision thresholds. CONCLUSIONS: The recommended 4-item integer-scored short-form PCL-5 generates diagnoses that closely parallel those of the full PCL-5, making it well-suited for screening.

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS: The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

Nicotine Dependence and Pre-Enlistment Suicidal Behavior Among U.S. Army Soldiers.

INTRODUCTION: Identification of modifiable risk factors for suicidal behaviors is a priority for the U.S. Army. This study investigated associations of nicotine dependence with suicidal behaviors among incoming soldiers. METHODS: Lifetime DSM-IV nicotine dependence, mental disorders, suicidal behaviors, and their ages of onset were retrospectively assessed in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) New Soldier Study. Discrete-time survival analysis of person-year data from 30,436 soldiers was performed to evaluate associations of nicotine dependence with subsequent suicidal ideation, plans, and attempts. Among respondents with lifetime ideation (n=4,060), models tested associations of nicotine dependence with progression from ideation to first onset of plan, from plan to first attempt, and, among ideators without plans, from ideation to first unplanned attempt. A hierarchy of models incorporated increasing controls for other risk factors. Data were collected in 2011-2012 and analyzed in 2017-2018. RESULTS: In models controlling for sociodemographic characteristics, nicotine dependence was associated with onset of all suicidal behaviors (AORs, 2.07-4.08, p<0.001) and with each type of progression of suicidal behavior (AORs, 1.48-2.44, p<0.005). After adjusting for childhood adversities and mental disorders, nicotine dependence remained associated with onset of ideation (AOR=1.27, 95% CI=1.10, 1.46, p=0.001) and attempt (AOR=1.83, 95% CI=1.41, 2.37, p<0.001); and with progression from ideation to unplanned attempt (AOR=2.03, 95% CI=1.17, 1.74, p<0.001). CONCLUSIONS: Nicotine dependence exhibited associations with onset of suicidal ideation and suicide attempt-and with progression from ideation to unplanned attempt-that were independent of other measured risk factors. Awareness of associations of nicotine dependence with suicidal behaviors may inform risk assessment, facilitate targeting of prevention efforts, and provide further impetus for reducing nicotine dependence.

Traumatic stress and accelerated DNA methylation age: A meta-analysis.

BACKGROUND: Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. METHODS: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. RESULTS: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. CONCLUSIONS: Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.

Medical-encounter mental health diagnoses, non-fatal injury and polypharmacy indicators of risk for accident death in the US Army enlisted soldiers, 2004-2009.

Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical-encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths.

Screening for Post-Traumatic Stress Disorder in a Civilian Emergency Department Population with Traumatic Brain Injury.

Post-traumatic stress disorder (PTSD) is a condition associated with traumatic brain injury (TBI). While the importance of PTSD and TBI among military personnel is widely recognized, there is less awareness of PTSD associated with civilian TBI. We examined the incidence and factors associated with PTSD 6 months post-injury in a civilian emergency department population using measures from the National Institute of Neurological Disorders and Stroke TBI Common Data Elements Outcome Battery. Participants with mild TBI (mTBI) from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with complete 6-month outcome batteries (n = 280) were analyzed. Screening for PTSD symptoms was conducted using the PTSD Checklist-Civilian Version. Descriptive measures are summarized and predictors for PTSD were examined using logistic regression. Incidence of screening positive for PTSD was 26.8% at 6 months following mTBI. Screening positive for PTSD was significantly associated with concurrent functional disability, post-concussive and psychiatric symptomatology, decreased satisfaction with life, and decreased performance in visual processing and mental flexibility. Multi-variable regression showed injury mechanism of assault (odds ratio [OR] 3.59; 95% confidence interval [CI] 1.69-7.63; p = 0.001) and prior psychiatric history (OR 2.56; 95% CI 1.42-4.61; p = 0.002) remained significant predictors of screening positive for PTSD, while education (per year OR 0.88; 95% CI 0.79-0.98; p = 0.021) was associated with decreased odds of PTSD. Standardized data collection and review of pre-injury education, psychiatric history, and injury mechanism during initial hospital presentation can aid in identifying patients with mTBI at risk for developing PTSD symptoms who may benefit from closer follow-up after initial injury care.

Alcohol Misuse and Co-Occurring Mental Disorders Among New Soldiers in the U.S. Army.

BACKGROUND: Problem drinking that predates enlistment into military service may contribute to the overall burden of alcohol misuse in the Armed Forces; however, evidence bearing on this issue is limited. This study examines prevalence and correlates of alcohol misuse among new U.S. Army soldiers. METHODS: Cross-sectional survey data were collected from soldiers reporting for basic combat training. The survey retrospectively assessed lifetime alcohol consumption and substance abuse/dependence, enabling estimation of the prevalence of lifetime binge drinking and heavy drinking in a sample of 30,583 soldiers and of probable alcohol use disorder (AUD) among 26,754 soldiers with no/minimal lifetime use of other drugs. Co-occurrence of mental disorders and other adverse outcomes with binge drinking, heavy drinking, and AUD was examined. Discrete-time survival analysis, with person-year the unit of analysis and a logistic link function, was used to estimate associations of AUD with subsequent onset of mental disorders and vice versa. RESULTS: Weighted prevalence of lifetime binge drinking was 27.2% (SE = 0.4) among males and 18.9% (SE = 0.7) among females; respective estimates for heavy drinking were 13.9% (SE = 0.3) and 9.4% (SE = 0.4). Among soldiers with no/minimal drug use, 9.5% (SE = 0.2) of males and 7.2% (SE = 0.5) of females had lifetime AUD. Relative to no alcohol misuse, binge drinking, heavy drinking, and AUD were associated with increased odds of all mental disorders and other adverse outcomes under consideration (adjusted odds ratios [AORs] = 1.5 to 4.6; ps < 0.001). Prior mental disorders and suicidal ideation were associated with onset of AUD (AORs = 2.3 to 2.8; ps < 0.001), and prior AUD was associated with onset of mental disorders and suicidal ideation (AORs = 2.0 to 3.2, ps < 0.005). CONCLUSIONS: Strong bidirectional associations between alcohol misuse and mental disorders were observed in a cohort of soldiers beginning Army service. Conjoint recognition of alcohol misuse and mental disorders upon enlistment may provide opportunities for risk mitigation early in a soldier's career.

"Soldier's Heart": A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder.

"Soldier's Heart," is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test (P = 3 × 10-54). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test (P = 1.8 × 10-16). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.