Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Childhood maltreatment and health in the UK Biobank: triangulation of outcome-wide and polygenic risk score analyses.

BACKGROUND: Childhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, including understudied physical health outcomes and bias due to unmeasured confounding. We address these limitations through a large-scale outcome-wide triangulation study. METHODS: We performed two outcome-wide analyses (OWAs) in the UK Biobank. First, we examined the relationship between self-reported maltreatment exposure (number of maltreatment types, via Childhood Trauma Screener) and 414 outcomes in a sub-sample of 157,316 individuals using generalized linear models ("observational OWA"). Outcomes covered a broad range of health themes including health behaviors, cardiovascular disease, digestive health, socioeconomic status, and pain. Second, we examined the relationship between a polygenic risk score for maltreatment and 298 outcomes in a non-overlapping sample of 243,006 individuals ("genetic OWA"). We triangulated results across OWAs based on differing sources of bias. RESULTS: Overall, 23.8% of the analytic sample for the observational OWA reported at least one maltreatment type. Of 298 outcomes examined in both OWAs, 25% were significant in both OWAs and concordant in the direction of association. Most of these were considered robust in the observational OWA according to sensitivity analyses and included outcomes such as marital separation (OR from observational OWA, ORo = 1.25 (95% CI: 1.21, 1.29); OR from genetic OWA, ORg = 1.06 (1.03, 1.08)), major diet changes due to illness (ORo = 1.27 (1.24, 1.29); ORg = 1.01 (1.00, 1.03)), certain intestinal diseases (ORo = 1.14 (1.10, 1.18); ORg = 1.03 (1.01, 1.06)), hearing difficulty with background noise (ORo = 1.11 (1.11, 1.12); ORg = 1.01 (1.00, 1.01)), knee arthrosis (ORo = 1.13 (1.09, 1.18); ORg = 1.03 (1.01, 1.05)), frequent sleeplessness (ORo = 1.21 (1.20, 1.23); ORg = 1.02 (1.01, 1.03)), and low household income (ORo = 1.28 (1.26, 1.31); ORg = 1.02 (1.01, 1.03)). Approximately 62% of results were significant in the observational OWA but not the genetic OWA, including numerous cardiovascular outcomes. Only 6 outcomes were significant in the genetic OWA and null in the observational OWA; these included diastolic blood pressure and glaucoma. No outcomes were statistically significant in opposite directions in the two analyses, and 11% were not significant in either OWA. CONCLUSIONS: Our findings underscore the far-reaching negative effects of childhood maltreatment in later life and the utility of an outcome-wide triangulation design with sensitivity analyses for improving causal inference.

Polygenic risk for major depression, attention deficit hyperactivity disorder, neuroticism, and schizophrenia are correlated with experience of intimate partner violence.

Research has suggested that mental illness may be a risk factor for, as well as a sequela of, experiencing intimate partner violence (IPV). The association between IPV and mental illness may also be due in part to gene-environment correlations. Using polygenic risk scores for six psychiatric disorders - attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia-and a combined measure of overall genetic risk for mental illness, we tested whether women's genetic risk for mental illness was associated with the experience of three types of intimate partner violence. In this cohort of women of European ancestry (N = 11,095), participants in the highest quintile of genetic risk for ADHD (OR range: 1.38-1.49), MDD (OR range: 1.28-1.43), neuroticism (OR range: (1.18-1.25), schizophrenia (OR range: 1.30-1.34), and overall genetic risk (OR range: 1.30-1.41) were at higher risk for experiencing more severe emotional and physical abuse, and, except schizophrenia, more severe sexual abuse, as well as more types of abuse and chronic abuse. In addition, participants in the highest quintile of genetic risk for neuroticism (OR = 1.43 95% CI: 1.18, 1.72), schizophrenia (OR = 1.33 95% CI: 1.10, 1.62), and the overall genetic risk (OR = 1.40 95% CI: 1.15, 1.71) were at higher risk for experiencing intimate partner intimidation and control. Participants in the highest quintile of genetic risk for ADHD, ASD, MDD, schizophrenia, and overall genetic risk, compared to the lowest quintile, were at increased risk for experiencing harassment from a partner (OR range: 1.22-1.92). No associations were found between genetic risk for BPD with IPV. A better understanding of the salience of the multiple possible pathways linking genetic risk for mental illness with risk for IPV may aid in preventing IPV victimization or re-victimization.

A flexible matching strategy for matched nested case-control studies.

PURPOSE: Individual matching in case-control studies improves statistical efficiency over random selection of controls but can lead to selection bias if cases are excluded due to the lack of appropriate controls or residual confounding with less strict matching criteria. We introduce flex matching, an algorithm using multiple rounds of control selection with successively relaxed matching criteria to select controls for cases. METHODS: We simulated exposure-disease relationships in multiple cohort data sets with a range of confounding scenarios and conducted 16,800,000 nested case-control studies, comparing random selection of controls, strict matching, and flex matching. We computed average bias and statistical efficiency in estimates of exposure-disease relationships under each matching strategy. RESULTS: On average, flex matching produced the least biased estimates of exposure-disease associations with the smallest standard errors. Strict matching algorithms that excluded cases for whom matched controls could not be identified produced biased estimates with larger standard errors. Estimates from studies with random assignment of controls were relatively unbiased, but the standard errors were larger than from studies using flex matching. CONCLUSIONS: Flex matching should be considered for case-control designs, especially for biomarker studies where matching on technical artifacts is necessary and maximizing efficiency is a priority.

Posttraumatic Stress Disorder, Depression, and Accelerated Aging: Leukocyte Telomere Length in the Nurses' Health Study II.

Background: Exposure to trauma, posttraumatic stress disorder (PTSD), and depression have been independently associated with leukocyte telomere length (LTL), a cellular marker of aging associated with mortality and age-related diseases. However, the joint contributions of trauma and its psychological sequelae on LTL have not been examined. Methods: We conducted an analysis of LTL in a subset of women from the Nurses' Health Study II (N = 1868). Lifetime exposure to traumatic events, PTSD, and depression was assessed with validated measures. DNA was extracted from peripheral blood leukocytes and telomere repeat copy number to single gene copy number was determined by quantitative real-time polymerase chain reaction telomere assay. Linear regression models assessed the association of trauma, PTSD, and depression with LTL after adjustment for health behaviors and medical conditions. Results: Trauma, PTSD, and depression were not independently associated with LTL in mutually adjusted models. However, individuals with severe psychological distress-characterized by comorbid PTSD and depression-had shorter LTL equivalent to being 7.62 years older (95% CI, 0.02 to 17.97) than participants who had never experienced a traumatic event and were not depressed. Further examination found only an association among individuals with the highest number of PTSD symptoms and comorbid depression equivalent to 9.71 additional years of aging (95% CI, 1.36 to 20.49). No effect was found among individuals meeting the minimum threshold for probable PTSD with comorbid depression. Conclusions: Severe psychological distress, as indicated by the presence of comorbid PTSD and depression, may be associated with shorter LTL.

Multiple types of distress are prospectively associated with increased risk of ovarian cancer.

BACKGROUND: Few modifiable risk factors for epithelial ovarian cancer have been identified. We and other investigators have found that individual psychosocial factors related to distress are associated with higher risk of ovarian cancer. The present study examined whether co-occurring distress-related factors are associated with ovarian cancer risk. METHODS: Five distress-related factors were measured repeatedly over 21 years of follow-up: depression, anxiety, social isolation, widowhood, and, in a subset or women, posttraumatic stress disorder (PTSD). Cox proportional hazards models estimate relative risks (RR) and 95% confidence intervals (CI) of ovarian cancer for a time-updated count of distress-related factors, in age-adjusted models, then further adjusted for ovarian cancer risk factors and behavior-related health risk factors. RESULTS: Across 1,193,927 person-years of follow-up, 526 incident ovarian cancers occurred. Women with ≥3 versus no distress-related psychosocial factors demonstrated increased ovarian cancer risk (HRage-adjusted = 1.71; 95% CI = 1.16, 2.52). No significant difference in ovarian cancer risk was observed in women with one or two versus no distress-related psychosocial factors. In the subsample with PTSD assessed, ≥3 versus no distress-related psychosocial factors was associated with twofold greater ovarian cancer risk (HRage-adjusted = 2.08, 95% CI = 1.01, 4.29). Further analysis suggested that women at highest ovarian cancer risk had PTSD co-occurring with any other distress-related factor (HR = 2.19, 95% CI = 1.20, 4.01). Adjusting for cancer risk factors and health behaviors minimally impacted risk estimates. CONCLUSIONS: Presence of multiple indicators of distress was associated with risk of ovarian cancer. When including PTSD as an indicator of distress, the association was strengthened.

Association of maternal polygenic risk scores for mental illness with perinatal risk factors for offspring mental illness.

We examined whether genetic risk for mental illness is associated with known perinatal risk factors for offspring mental illness to determine whether gene-environmental correlation might account for the associations of perinatal factors with mental illness. Among 8983 women with 19,733 pregnancies, we found that genetic risk for mental illness was associated with any smoking during pregnancy [attention-deficit hyperactivity disorder (ADHD) and overall genetic risk], breast-feeding for less than 1 month (ADHD, depression, and overall genetic risk), experience of intimate partner violence in the year before the birth (depression and overall genetic risk), and pregestational overweight or obesity (bipolar disorder). These results indicate that genetic risk may partly account for the association between perinatal conditions and mental illness in offspring.

Trauma, psychological distress and markers of systemic inflammation among US women: A longitudinal study.

BACKGROUND: Prior evidence links posttraumatic stress disorder (PTSD) and depression, separately, with chronic inflammation. However, whether effects are similar across each independently or potentiated when both are present is understudied. We evaluated combined measures of PTSD and depression in relation to inflammatory biomarker concentrations. METHODS: Data are from women (n's ranging 628-2797) in the Nurses' Health Study II. Trauma exposure, PTSD, and depression symptoms were ascertained using validated questionnaires. We examined (a) a continuous combined psychological distress score summing symptoms for PTSD and depression, and (b) a categorical cross-classified measure of trauma/PTSD symptoms/depressed mood status (reference group: no trauma or depressed mood). Three inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor alpha receptor 2 [TNFR2]) were assayed from at least one of two blood samples collected 10-16 years apart. We examined associations of our exposures with levels of each biomarker concentration (log-transformed and batch-corrected) as available across the two time points (cross-sectional analyses; CRP, IL-6 and TNFR2) and with rate of change in biomarkers across time (longitudinal analyses; CRP and IL-6) using separate linear mixed effects models. RESULTS: In sociodemographic-adjusted models accounting for trauma exposure, a one standard deviation increase in the continuous combined psychological distress score was associated with 10.2% (95% confidence interval (CI): 5.2-15.4%) higher CRP and 1.5% (95% CI: 0.5-2.5%) higher TNFR2 concentrations cross-sectionally. For the categorical exposure, women with trauma/PTSD symptoms/ depressed mood versus those with no trauma or depressed mood had 29.5% (95% CI: 13.3-47.9%) higher CRP and 13.1% (95% CI: 5.1-21.7%) higher IL-6 cross-sectionally. In longitudinal analysis, trauma/PTSD symptoms/depressed mood was associated with increasing CRP levels over time. CONCLUSIONS: High psychological distress levels with trauma exposure is associated with elevated inflammation and is a potential biologic pathway by which distress can impact development of inflammatory-related chronic diseases, such as cardiovascular disease. Considering multiple forms of distress in relation to these pathways may provide greater insight into who is at risk for biologic dysregulation and later susceptibility to chronic diseases.

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.

Trauma, Post-Traumatic Stress Disorder, and Treatment Among Middle-Aged and Older Women in the Nurses' Health Study II.

OBJECTIVE: Trauma and post-traumatic stress disorder (PTSD) are common among women and associated with negative health outcomes across the life course. Relatively few studies, however, have examined the epidemiology of trauma, PTSD, and treatment among middle-aged and older civilian women, who are at elevated risk for adverse health outcomes. We aimed to characterize trauma, PTSD, and trauma-related treatment prevalence and correlates in a large cohort of middle-aged and older women. DESIGN: Cross-sectional, nested substudy within the Nurses' Health Study II cohort. SETTING: United States, 2018-2020. PARTICIPANTS: 33,327 current or former nurses, aged 53-74 years. MEASUREMENTS: 16-item modified version of the Brief Trauma Questionnaire; modified PTSD Checklist for the Diagnostic and Statistical Manual, Version 5. RESULTS: The majority (82.2%) of women reported one or more lifetime traumas. The most common trauma types were unexpected death of a loved one (44.9%) and interpersonal violence (43.5%). Almost 30% reported occupational (nursing-related) trauma. Among the trauma-exposed, 10.5% met criteria for lifetime PTSD and 1.5% had past-month PTSD. One-third of lifetime PTSD cases were due to interpersonal violence event types. One-third of women with lifetime PTSD-and nearly half of those with PTSD from a nursing-related trauma-reported never receiving trauma-related treatment. Women aged 65 years and older with PTSD were less likely to be in treatment than those aged less than 65 years. CONCLUSION: History of trauma and PTSD is prevalent in this population, and a treatment gap persists. Addressing this treatment gap is warranted, particularly among older women and those with nursing-related trauma.

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.

The impact of psychopathology, social adversity and stress-relevant DNA methylation on prospective risk for post-traumatic stress: A machine learning approach.

BACKGROUND: A range of factors have been identified that contribute to greater incidence, severity, and prolonged course of post-traumatic stress disorder (PTSD), including: comorbid and/or prior psychopathology; social adversity such as low socioeconomic position, perceived discrimination, and isolation; and biological factors such as genomic variation at glucocorticoid receptor regulatory network (GRRN) genes. This complex etiology and clinical course make identification of people at higher risk of PTSD challenging. Here we leverage machine learning (ML) approaches to identify a core set of factors that may together predispose persons to PTSD. METHODS: We used multiple ML approaches to assess the relationship among DNA methylation (DNAm) at GRRN genes, prior psychopathology, social adversity, and prospective risk for PTS severity (PTSS). RESULTS: ML models predicted prospective risk of PTSS with high accuracy. The Gradient Boost approach was the top-performing model with mean absolute error of 0.135, mean square error of 0.047, root mean square error of 0.217, and R2 of 95.29%. Prior PTSS ranked highest in predicting the prospective risk of PTSS, accounting for >88% of the prediction. The top ranked GRRN CpG site was cg05616442, in AKT1, and the top ranked social adversity feature was loneliness. CONCLUSION: Multiple factors including prior PTSS, social adversity, and DNAm play a role in predicting prospective risk of PTSS. ML models identified factors accounting for increased PTSS risk with high accuracy, which may help to target risk factors that reduce the likelihood or course of PTSD, potentially pointing to approaches that can lead to early intervention. LIMITATION: One of the limitations of this study is small sample size.

Polygenic risk for autism, attention-deficit hyperactivity disorder, schizophrenia, major depressive disorder, and neuroticism is associated with the experience of childhood abuse.

People who experience childhood abuse are at increased risk of mental illness. Twin studies suggest that inherited genetic risk for mental illness may account for some of these associations. Yet, the hypothesis that individuals who have experienced childhood abuse may carry genetic loading for mental illness has never been tested with genetic data. Using polygenic risk scores for six psychiatric disorders-attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia-we tested whether genetic risk for mental illness was associated with increased risk of experiencing three types of childhood abuse: physical/emotional abuse, physical assault, and sexual abuse, in a cohort of white non-Hispanic women (n = 11,315). ADHD and MDD genetic risk scores were associated with a higher risk of experiencing each type of childhood abuse, while neuroticism, schizophrenia, BPD, and ASD genetic scores were associated with a higher risk of experiencing physical/emotional abuse and physical assault, but not sexual abuse. Sensitivity analyses examining potential bias from the differential recall of childhood trauma, parental socioeconomic status, and population stratification were consistent with the main findings. A one-standard-deviation increase in genetic risk for mental illness was associated with a modestly elevated risk of experiencing childhood abuse (OR range: 1.05-1.19). Therefore, inherited genetic risk may partly account for the association of childhood abuse with mental illness. In addition, future treatments for mental illness will benefit from taking into consideration the co-occurrence of childhood trauma and genetic loading.

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Posttraumatic stress disorder symptom trajectories within the first year following emergency department admissions: pooled results from the International Consortium to predict PTSD.

BACKGROUND: Research exploring the longitudinal course of posttraumatic stress disorder (PTSD) symptoms has documented four modal trajectories (low, remitting, high, and delayed), with proportions varying across studies. Heterogeneity could be due to differences in trauma types and patient demographic characteristics. METHODS: This analysis pooled data from six longitudinal studies of adult survivors of civilian-related injuries admitted to general hospital emergency departments (EDs) in six countries (pooled N = 3083). Each study included at least three assessments of the clinician-administered PTSD scale in the first post-trauma year. Latent class growth analysis determined the proportion of participants exhibiting various PTSD symptom trajectories within and across the datasets. Multinomial logistic regression analyses examined demographic characteristics, type of event leading to the injury, and trauma history as predictors of trajectories differentiated by their initial severity and course. RESULTS: Five trajectories were found across the datasets: Low (64.5%), Remitting (16.9%), Moderate (6.7%), High (6.5%), and Delayed (5.5%). Female gender, non-white race, prior interpersonal trauma, and assaultive injuries were associated with increased risk for initial PTSD reactions. Female gender and assaultive injuries were associated with risk for membership in the Delayed (v. Low) trajectory, and lower education, prior interpersonal trauma, and assaultive injuries with risk for membership in the High (v. Remitting) trajectory. CONCLUSIONS: The results suggest that over 30% of civilian-related injury survivors admitted to EDs experience moderate-to-high levels of PTSD symptoms within the first post-trauma year, with those reporting assaultive violence at increased risk of both immediate and longer-term symptoms.

Posttraumatic Stress Disorder and Likelihood of Hormone Therapy Use among Women in the Nurses' Health Study II: A 26-Year Prospective Analysis.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years. METHODS: Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989-2002 vs. 2003-2015). RESULTS: Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1-3 PTSD symptoms [95% confidence interval (CI), 1.13-1.22] and 1.31 for those with trauma/4-7 PTSD symptoms (95% CI, 1.25-1.36; P trend < 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline. CONCLUSIONS: Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose-response manner. IMPACT: MHT may be a pathway linking PTSD to altered chronic disease risk. It is important to understand why women with PTSD initiate MHT use.

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.

An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression.

OBJECTIVE: Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression. METHODS: Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression. RESULTS: Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53). CONCLUSIONS: Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry.

Correction to: Evaluating a screener to quantify PTSD risk using emergency care information: a proof of concept study.

An amendment to this paper has been published and can be accessed via the original article.

Evaluating a screener to quantify PTSD risk using emergency care information: a proof of concept study.

BACKGROUND: Previous work has indicated that post-traumatic stress disorder (PTSD) symptoms, measured by the Clinician-Administered PTSD Scale (CAPS) within 60 days of trauma exposure, can reliably produce likelihood estimates of chronic PTSD among trauma survivors admitted to acute care centers. Administering the CAPS is burdensome, requires skilled professionals, and relies on symptoms that are not fully expressed upon acute care admission. Predicting chronic PTSD from peritraumatic responses, which are obtainable upon acute care admission, has yielded conflicting results, hence the rationale for a stepwise screening-and-prediction practice. This work explores the ability of peritraumatic responses to produce risk likelihood estimates of early CAPS-based PTSD symptoms indicative of chronic PTSD risk. It specifically evaluates the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) as a risk-likelihood estimator. METHODS: We used individual participant data (IPD) from five acute care studies that used both the PDEQ and the CAPS (n = 647). Logistic regression calculated the probability of having CAPS scores ≥ 40 between 30 and 60 days after trauma exposure across the range of initial PDEQ scores, and evaluated the added contribution of age, sex, trauma type, and prior trauma exposure. Brier scores, area under the receiver-operating characteristic curve (AUC), and the mean slope of the calibration line evaluated the accuracy and precision of the predicted probabilities. RESULTS: Twenty percent of the sample had CAPS ≥ 40. PDEQ severity significantly predicted having CAPS ≥ 40 symptoms (p < 0.001). Incremental PDEQ scores produced a reliable estimator of CAPS ≥ 40 likelihood. An individual risk estimation tool incorporating PDEQ and other significant risk indicators is provided. CONCLUSION: Peritraumatic reactions, measured here by the PDEQ, can reliably quantify the likelihood of acute PTSD symptoms predictive of chronic PTSD and requiring clinical attention. Using them as a screener in a stepwise chronic PTSD prediction strategy may reduce the burden of later CAPS-based assessments. Other peritraumatic metrics may perform similarly and their use requires similar validation. TRIAL REGISTRATION: Jerusalem Trauma Outreach and Prevention Study (J-TOPS): NCT00146900.