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.

Cardiorespiratory Fitness Is Associated With Better Cardiometabolic Health and Lower PTSD Severity in Post-9/11 Veterans.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular and metabolic diseases and physical inactivity. Cardiorespiratory fitness (CRF), which is modifiable by physical activity, is a strong independent predictor of cardiometabolic health. However, the relationship between CRF and cardiometabolic health in veterans with PTSD is unknown. Thus, this study aimed to explore the cross-sectional relationships among CRF, indices of cardiometabolic health (ie, HbA1c, blood lipids, blood pressure, waist-hip ratio, and body mass index), and PTSD severity in veterans with PTSD. MATERIALS AND METHODS: This study was approved by the local Institutional Review Board. All participants were informed of the study risks and provided consent prior to participation. Participants (n = 13) completed a cardiopulmonary exercise test, a fasting blood draw, and the Clinician Administered PTSD Scale. Correlations between CRF and cardiometabolic health were examined with Spearman's rank correlations, and differences in PTSD symptom severity were explored as a function of CRF (ie, low-to-moderate vs. high CRF), using multiple linear regression. RESULTS: Peak oxygen uptake ($\dot{\mathrm{V}}$O2peak) was correlated with high-density lipoproteins rho = 0.60, P = 0.04 and diastolic blood pressure rho = -0.56, P = 0.05. Ventilatory threshold was correlated with HbA1c rho = -0.61, P = 0.03 and diastolic blood pressure rho = -0.56, P = 0.05. Higher CRF was associated with lower total PTSD severity standardized ß = -0.84, P = 0.01, adjusted R2 = 0.47, total Cluster C symptoms (avoidance/numbing) ß = -0.71, P = 0.02, adjusted R2 = 0.49, and total Cluster D symptoms (hyperarousal) ß = -0.89, P = 0.01, adjusted R2 = 0.41, while adjusting for age and smoking status. CONCLUSIONS: These preliminary findings suggest that CRF and by proxy physical activity may be important factors in understanding the increased risk of cardiovascular and metabolic disease associated with PTSD.

The goddess who spins the thread of life: Klotho, psychiatric stress, and accelerated aging.

BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. METHODS: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.

Tobacco dependence is associated with increased risk for multi-morbid clustering of posttraumatic stress disorder, depressive disorder, and pain among post-9/11 deployed veterans.

RATIONALE: Tobacco use is highly prevalent among individuals with posttraumatic stress disorder (PTSD), depressive disorders, and pain. Research has revealed pairwise relationships among these conditions but has not examined more complex relationships that may influence symptom severity, chronicity, and treatment outcome. OBJECTIVE: To examine the clustering of current PTSD, depressive disorders, and clinically significant pain according to current tobacco use and dependence among post-9/11 deployed veterans. METHODS: Logistic regression was used to examine the clustering of these conditions in relationship to current tobacco use/dependence, while adjusting for age and total combat exposure, in 343 post-9/11 deployed veterans enrolled in the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort (Mage = 32.1 + 8.3 years; 38% current tobacco use; 25% low and 12% moderate/high tobacco dependence). RESULTS: A three-way clustering of PTSD, depressive disorder, and pain was more likely than any single or pairwise combination of these conditions in moderate/high tobacco-dependent veterans compared to tobacco non-users (adjusted ORs = 3.50 to 4.18). This multi-morbidity cluster also was associated with increased PTSD severity. CONCLUSIONS: Moderate to high dependence on tobacco is associated with substantially increased clustering of PTSD, depression, and clinically significant pain in veterans. Research examining synergistic interactions among these conditions, biological vulnerabilities shared among them, and the direct impact of tobacco use on the pathophysiology of PTSD, depression, and pain is needed. The results of such work may spur development of more effective integrated treatments to reduce the negative impact of these multi-morbid conditions on veterans' wellbeing and long-term health.

Detecting cognitive impairment in individuals at risk for cardiovascular disease: the "Clock-in-the-Box" screening test.

OBJECTIVE: The purpose of this study was to evaluate the performance on the Clock-in-the-Box (CIB), a screening measure for cognitive function, relative to neuropsychological testing in an older population with cardiovascular risk. METHODS: A prospective cohort of older patients (>50 years) with cardiovascular risk was recruited to perform the CIB and complete a brief neuropsychological battery consisting of Trailmaking tests, the Hopkins Verbal Learning Test (HVLT), and fluency tasks. Performance on the CIB was scored according to standard criteria (range 0-8, 0-worst). The performance on the total CIB, working memory subscale (CIB-WM), and planning/organization (COB-PO) was compared to neuropsychological measures. RESULTS: The cohort (n = 127) was older (age 67 ± 7 years) and diverse with 33% female (n = 42) and 42% non-white race (n = 53). Cardiac risk factors were prevalent: hypertension (83%), hyperlipidemia (74%), overweight (84%), diabetes (48%), prior cardiac disease (39%), and smoking (11%). The CIB (mean 6.5 ± 1.3) took 84 ± 21 s on average to complete and had good inter-rater reliability (κ = 0.809, p < 0.01). The CIB-WM subscale was significantly correlated with performance on Trailmaking B and HVLT learning, recall, and recognition. The CIB-PO subscale was significantly associated with semantic and phonemic fluency, Trailmaking B, and HVLT learning and recall. In regression modeling, CIB-WM significantly predicted performance on HVLT learning, recall, and retention. CIB-PO subscale predicted performance on Trailmaking B, HVLT learning, and HVLT recall. CONCLUSIONS: The CIB is a brief cognitive screening instrument with good reliability and predictive validity in a CV risk population. The CIB-WM and CIB-PO subscales could provide utility for clinicians.

Cognitive screening in community-dwelling elders: performance on the clock-in-the-box.

BACKGROUND: The Clock-in-the-Box is a rapid (2-minute) cognitive screening tool. The purpose of this study was to compare the Clock-in-the-Box with the Mini-Mental State Exam and neuropsychologic tests; to determine Clock-in-the-Box score normative values by age and education group; and to determine if the Clock-in-the-Box score is associated with measures of physical function. METHODS: Community-dwelling older participants in the Boston area were recruited for a prospective, longitudinal study in which they completed a variety of cognitive and functional assessments. RESULTS: At baseline, participants (n=798; mean age [± standard deviation]=78.2 [±5.5] years; 14 [±3] mean years of education) completed in-home assessments of cognition (Clock-in-the-Box and Mini-Mental State Exam), measures of independent function (Activities of Daily Living and Instrumental Activities of Daily Living), and measures of physical function (Short Physical Performance Battery). The mean Mini-Mental State Exam score was 27.1 (±1.6; range 0-30 [0 worst]), and the mean Clock-in-the-Box score was 6.2 (±1.6; range 0-8 [0 worst]). Performance on the Clock-in-the-Box was correlated (Spearman) with the Mini-Mental State Exam (r=0.49, P<.001) and neuropsychologic measures (r=0.37-0.50; P<.001). Higher Clock-in-the-Box score was significantly associated with no difficulty in Activities of Daily Living (χ(2) = 39.6, P<.001) and Instrumental Activities of Daily Living (χ(2) = 35.5, P<.001). In addition, higher Clock-in-the-Box scores were associated with higher scores on the Short Physical Performance Battery (F=5.4, P<.001). CONCLUSION: The Clock-in-the-Box is a brief cognitive screening test that is correlated with the Mini-Mental State Exam, neuropsychologic tests, and measures of independent and physical function in community-dwelling older adults.