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.

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 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.

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.

Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging.

Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood. Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects. Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed. Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium.

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.

Posttraumatic stress disorder and accelerated aging: PTSD and leukocyte telomere length in a sample of civilian women.

BACKGROUND: Studies in male combat veterans have suggested posttraumatic stress disorder (PTSD) is associated with shorter telomere length (TL). We examined the cross-sectional association of PTSD with TL in women exposed to traumas common in civilian life. METHODS: Data are from a substudy of the Nurses' Health Study II (N = 116). PTSD and subclinical PTSD were assessed in trauma-exposed women using diagnostic interviews. An array of health behaviors and conditions were assessed. DNA was extracted from peripheral blood leukocytes (collected 1996-1999). Telomere repeat copy number to single gene copy number (T/S) was determined by quantitative real-time PCR telomere assay. We used linear regression models to assess associations and examine whether a range of important health behaviors (e.g., cigarette smoking) and medical conditions (e.g., hypertension) previously associated with TL might explain a PTSD-TL association. We further examined whether type of trauma exposure (e.g., interpersonal violence) was associated with TL and whether trauma type might explain a PTSD-TL association. RESULTS: Relative to not having PTSD, women with a PTSD diagnosis had shorter log-transformed TL (ß = -.112, 95% confidence interval (CI) = -0.196, -0.028). Adjustment for health behaviors and medical conditions did not attenuate this association. Trauma type was not associated with TL and did not account for the association of PTSD with TL. CONCLUSIONS: Our results add to growing evidence that PTSD may be associated with more rapid cellular aging as measured by telomere erosion. Moreover, the association could not be explained by health behaviors and medical conditions assessed in this study, nor by type of trauma exposure.