Genetic risk for hospitalization of African American patients with severe mental illness reveals HLA loci.

Background: Mood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI). Methods: Patients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package. Results: Genome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D (UBD/FAT10) gene (rs362514, p=9.43x10-9) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10-3) and HLA-C*06:02 (OR=1.04, p=1.5x10-3). Two other genes (VSP13D and TSPAN9), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses. Conclusion: We observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI.

Association between dimensions of trauma-related psychopathology and asthma in trauma-exposed women.

Introduction: Exposure to traumatic events and stressful life experiences are associated with a wide range of adverse mental and physical health outcomes. Studies have found post-traumatic stress disorder (PTSD), depression, and anxiety sensitivity occurrence to be common in addition to inflammatory diseases like asthma, especially in women. Moreover, overlapping neurobiological mechanisms have been linked to both PTSD and asthma. Methods: In the current study, n = 508 women reported on presence of lifetime asthma diagnosis and symptoms of trauma-related psychopathology including PTSD and depression. A separate group of female participants (n = 64) reported on asthma, PTSD, depression and anxiety sensitivity, and underwent functional MRI scans during a fearful faces task, and their anterior insula responses were analyzed. Results: Overall, PTSD and depression severity were significantly higher in those with asthma versus those without asthma. There was a positive association between anterior insula response to social threat cues and depression symptoms only among individuals without a lifetime presence of asthma. Discussion: These findings provide continued evidence on the interactions between stress, neural mechanisms involved in interoception and salience detection, and trauma-related psychopathology.

Indirect Effects of Racial Discrimination on Health Outcomes Through Prefrontal Cortical White Matter Integrity.

BACKGROUND: Racial discrimination is consistently associated with adverse health outcomes and has been linked to structural decrements in brain white matter. However, it is unclear whether discrimination-related neuroplastic changes could indirectly affect health outcomes. Our goal was to evaluate indirect associations of racial discrimination on health outcomes through white matter microstructure in a sample of trauma-exposed Black women. METHODS: A trauma study in an urban hospital setting recruited 79 Black women who received a history and physical examination to assess medical disorders (compiled into a summed total of disorder types). Participants reported on experiences of racial discrimination and underwent diffusion tensor imaging; fractional anisotropy values were extracted from white matter pathways previously linked to racial discrimination (corpus callosum, including the body and genu; anterior cingulum bundle; and superior longitudinal fasciculus) and entered into mediational models. RESULTS: Indirect effects of racial discrimination on medical disorders through left anterior cingulum bundle fractional anisotropy were significant (ß = 0.07, SE = 0.04, 95% CI [0.003, 0.14]) after accounting for trauma and economic disadvantage. Indirect effects of racial discrimination on medical disorders through corpus callosum genu fractional anisotropy were also significant (ß = 0.08, SE = 0.04, 95% CI [0.01, 0.16]). CONCLUSIONS: Racial discrimination may increase risk for medical disorders via neuroplastic effects on microstructural integrity of stress-sensitive prefrontal white matter tracts. Racial discrimination-related changes in these tracts may affect health behaviors, which, in turn, influence vulnerability for medical disorders. These data highlight the connections between racial discrimination, prefrontal white matter connections, and incidence of medical disorders in Black Americans.

Vagal control moderates the association between endothelial function and PTSD symptoms in women with T2DM.

Background: Individuals with posttraumatic stress disorder (PTSD) are more likely to present with metabolic diseases such as type-2 diabetes mellitus (T2DM), and cardiovascular dysfunction has been implicated in this link. These diseases disproportionately affect women and individuals exposed to chronic environmental stressors (e.g., community violence, poverty). We examined associations among PTSD, cardiovascular indices, and metabolic function in highly trauma-exposed Black women with T2DM. Methods: Participants (N = 80) were recruited for a follow-up study of stress and T2DM as part of the Grady Trauma Project. PTSD symptoms were assessed with the Clinician Administered PTSD Scale (CAPS-IV). Cardiovascular indices included heart rate (HR), blood pressure (BP), respiratory sinus arrhythmia (RSA), and endothelial function (assessed via flow-mediated dilation; FMD). An oral glucose tolerance test was used as an indicator of metabolic function. Results: Of the cardiovascular indices, only FMD was significantly associated with PTSD symptoms (CAPS Avoidance symptoms; ß = -0.37, p = .042), and glucose tolerance (ß = -0.44, p = .019), controlling for age and body mass index. The association between FMD and PTSD Avoidance was moderated by RSA such that the effect of FMD was only significant at low levels of RSA (simple slopes ß = -0.87, p = .004). Conclusions: Our results indicate that endothelial function is significantly related to PTSD and glucose tolerance, over and above other cardiovascular measures (HR, BP, RSA). Further, our results suggest that low RSA may be a risk factor for the link between poor endothelial function and PTSD in women with T2DM.

Inflammation, amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in African American women recruited from an inner-city hospital: Preliminary results.

Inflammatory stimuli have been shown to impact brain regions involved in threat detection and emotional processing including amygdala and ventromedial prefrontal cortex (vmPFC), and to increase anxiety. Biomarkers of endogenous inflammation, including inflammatory cytokines and C-reactive protein (CRP), are reliably elevated in a subset of patients with depression and anxiety-related disorders such as post-traumatic stress disorder (PTSD), and have been associated with high anxiety in population studies. We previously reported that plasma CRP and cytokines in patients with depression were negatively correlated with resting-state functional connectivity (FC) between right amygdala and vmPFC, as assessed using both ROI to voxel-wise and targeted FC approaches, in association with symptoms of anxiety, particularly in patients with comorbid anxiety disorders or PTSD. To determine whether relationships between inflammation, right amygdala-vmPFC FC, and anxiety are reproducible across patient samples and research settings, we employed an a priori, hypothesis-driven approach to examine relationships between inflammation, targeted right amygdala-vmPFC FC and anxiety in a cohort of African American (AA) women (n = 54) recruited from an inner-city hospital population reliably found to have higher levels of inflammation (median CRP âˆ¼ 4 mg/L) as well as symptoms of anxiety, depression and PTSD. Higher concentrations of plasma CRP were associated with lower right amygdala-vmPFC FC (r = -0.32, p = 0.017), and this relationship remained significant when controlling for age, body mass index and number of lifetime trauma events experienced, as well as severity of PTSD and depression symptoms (all p < 0.05). This amygdala-vmPFC FC was similarly associated with a composite score of three inflammatory cytokines in a subset of women where plasma was available for analysis (n = 33, r = -0.33, p = 0.058; adjusted r = -0.43, p = 0.026 when controlling for covariates including PTSD and depression symptom severity). Lower right amygdala-vmPFC FC was in turn associated with higher levels of anxiety reported to be generally experienced on the State-Trait Anxiety Inventory, trait component (adjusted r = -0.32, p = 0.039 when controlling for covariates). Exploratory analyses also revealed a negative correlation between severity of childhood maltreatment and right amygdala-vmPFC FC (r = -0.32, p = 0.018) that was independent of CRP and its association with FC, as well as an association between low amygdala-vmPFC FC and severity of PTSD symptoms, specifically the re-experiencing/intrusive symptom subscale (adjusted r = -0.32, p = 0.028 when controlling for covariates). While CRP was not linearly associated with either anxiety or PTSD symptoms, CRP concentrations were higher in women reporting clinically significant anxiety or PTSD symptom severity when these symptoms were considered together (both p < 0.05), but with no interaction. These results support our primary hypothesis that higher inflammation was associated with lower amygdala-vmPFC FC, a relationship that was detected using a hypothesis-driven, targeted approach. Findings also support that this phenotype of high CRP and low vmPFC FC was observed in association with anxiety in primary analyses, as well as symptoms of PTSD in exploratory analyses, in a cohort recruited from an inner-city population of AA women enriched for high inflammation, history of trauma exposure, and symptom severity. Larger, longitudinal samples are required to fully tease apart causal relationships between inflammatory biomarkers, FC and PTSD-related symptoms in future studies.

Developmental Timing of Trauma in Women Predicts Unique Extracellular Vesicle Proteome Signatures.

BACKGROUND: Exposure to traumatic events is a risk factor for negative physical and mental health outcomes. However, the underlying biological mechanisms that perpetuate these lasting effects are not known. METHODS: We investigated the impact and timing of sexual trauma, a specific type of interpersonal violence, experienced during key developmental windows of childhood, adolescence, or adulthood on adult health outcomes and associated biomarkers, including circulating cell-free mitochondrial DNA levels and extracellular vesicles (EVs), in a predominantly Black cohort of women (N = 101). RESULTS: Significant changes in both biomarkers examined, circulating cell-free mitochondrial DNA levels and EV proteome, were specific to developmental timing of sexual trauma. Specifically, we identified a large number of keratin-related proteins from EVs unique to the adolescent sexual trauma group. Remarkably, the majority of these keratin proteins belong to a 17q21 gene cluster, which suggests a potential local epigenetic regulatory mechanism altered by adolescent trauma to impact keratinocyte EV secretion or its protein cargo. These results, along with changes in fear-potentiated startle and skin conductance detected in these women, suggest that sexual violence experienced during the specific developmental window of adolescence may involve unique programming of the skin, the body's largest stress organ. CONCLUSIONS: Together, these descriptive studies provide novel insight into distinct biological processes altered by trauma experienced during specific developmental windows. Future studies will be required to mechanistically link these biological processes to health outcomes.

Promoting resilience in persons with serious mental health conditions during the Coronavirus pandemic.

This article highlights the profound and far-reaching impact of the Coronavirus disease 2019 (COVID-19) health crisis on persons with serious mental health conditions. To understand and mitigate against the negative effects of the crisis on this population, we offer a resilience intervention framework that attends to three key resilience processes, namely control, coherence, and connectedness (3Cs). We then detail interventions and associated evidence-informed intervention strategies at the individual, interpersonal, and systemic levels that behavioral health professionals can employ to bolster each of the 3Cs for persons with serious mental health conditions. These intervention strategies, which must be implemented in a flexible manner, are designed to enhance the biopsychosocial functioning of persons with serious mental health conditions during the COVID-19 pandemic and beyond and strengthen their interpersonal and systemic environments. We conclude with recommendations for future directions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Heart rate variability and HbA1c predict plasma interleukin-6 response to psychosocial stress challenge in trauma-exposed women with type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States. Although cardiovascular autonomic functioning, blood glucose control, and inflammation are known to play a role in T2DM, the interaction between these variables remains largely unexplored, particularly in the context of stress. To address this gap, we examined the relationship between these variables in a sample that is uniquely vulnerable to the health consequences of T2DM. METHODS: Participants were 37 trauma-exposed Black women with a diagnosis of T2DM. High frequency heart rate variability (HF-HRV), blood glucose control (HbA1c), and a stressor-evoked biomarker of inflammation (interleukin 6; IL-6) were obtained as part of a larger study of the genetic risk factors for and consequences of trauma exposure. RESULTS: The interaction of HbA1c and HF-HRV was significantly associated with IL-6 response calculated as area under the curve with respect to ground. Post-hoc simple slopes analyses revealed HbA1c, rather than HF-HRV, as the moderator in this association such that higher HF-HRV conferred higher circulating levels of IL-6 only in the presence of lower HbA1c, (ߠ​= â€‹0.60, t â€‹= â€‹3.51, p â€‹= â€‹.001). CONCLUSIONS: Cardiovascular autonomic functioning and blood glucose control were significantly associated with stressor-evoked IL-6 responses when controlling for BMI and age. Moreover, the association between cardiovascular autonomic functioning and inflammation varied at different levels of HbA1c. This highlights the possibility that individuals with trauma exposure and T2DM may benefit from stratification by HbA1c levels for research analysis and treatment decision making.

Subjective Social Status Is Associated with Dysregulated Eating Behaviors and Greater Body Mass Index in an Urban Predominantly Black and Low-Income Sample.

BACKGROUND: Higher subjective social status (SSS) or a person's perception of their social standing is related to better health outcomes, but few studies examined SSS in relation to obesity. Emotional eating and food addiction have been linked to obesity. Some studies indicated that manipulating SSS may lead to altered food intake, but the relationship between SSS and dysregulated eating, such as emotional eating and food addiction (FA), has not been examined. The goal of this study was to examine the associations between SSS in the community and the larger society, dysregulated eating (emotional eating and FA), and body mass index (BMI) in a majority racial minority sample. METHODS: The participants (N = 89; 93% Black, 86% women, and 56% with obesity; 72% income lower than USD 2000), recruited from a publicly funded hospital in Atlanta, GA, completed the MacArthur Scale, Dutch Eating Behaviors Questionnaire, Yale Food Addiction Scale, Beck Depression Inventory, PTSD Symptom Checklist, and demographics questionnaire. RESULTS: Twenty-two percent of the sample met the criteria for FA; those with FA had significantly higher BMI than those without (p = 0.018). In the hierarchical linear regression, the SSS community (but not in society) predicted higher severity of emotional eating (ß = 0.26, p = 0.029) and FA (ß = 0.30, p = 0.029), and higher BMI (ß = 0.28, p = 0.046), independent from depression and PTSD symptoms. CONCLUSIONS: The findings indicate that, among Black individuals with predominantly low income in the U.S., perceived role in their community is associated with eating patterns and body mass. Given the small sample size, the results should be interpreted with caution.

Emotion dysregulation and dissociation contribute to decreased heart rate variability to an acute psychosocial stressor in trauma-exposed Black women.

Reduced heart rate variability (HRV) in response to stress is a biomarker of emotion dysregulation (ED) and is related to posttraumatic stress disorder (PTSD), yet less is known about its role with dissociation in trauma-exposed adults. The goals of the current study were to examine unique patterns of associations between ED, dissociation, and PTSD with HRV at 15, 30, and 45 min (T1, T2, T3) following an acute psychosocial stressor task in a sample of 49 trauma-exposed, urban-dwelling Black women. Associations with baseline psychophysiology measures were also examined. ED and dissociation were assessed using self-report; PTSD was determined using a semi-structured interview. Heart rate (HR) and HRV, indexed with low frequency/high frequency (LF/HF) ratio and respiratory sinus arrhythmia (RSA), were measured with electrocardiogram recordings. ED and dissociation were positively correlated with LF/HF ratio at T3 (p < .05). There were no significant differences between individuals with PTSD versus those without PTSD in HR or HRV following acute stressor; PTSD diagnosis was related to higher HR at baseline. Latent growth modeling revealed that ED was associated with higher LF/HF ratio directly following acute stressor, while dissociation was associated with increase in LF/HF ratio over time. These findings demonstrate that ED is related to higher sympathetic reactivity for a prolonged period of time following stress exposure, while dissociation shows a delayed association with LF/HF ratio, suggesting a distinct impaired parasympathetic activation pattern exists for dissociation.

Posttraumatic Stress Disorder and Cardiovascular Disease: State of the Science, Knowledge Gaps, and Research Opportunities.

Posttraumatic stress disorder (PTSD) is characterized by a persistent maladaptive reaction after exposure to severe psychological trauma. Traumatic events that may precipitate PTSD include violent personal assaults, natural and human-made disasters, and exposure to military combat or warfare. There is a growing body of evidence for associations of PTSD with major risk factors for cardiovascular disease (CVD), such as hypertension and diabetes, as well as with major CVD outcomes, such as myocardial infarction and heart failure. However, it is unclear whether these associations are causal or confounded. Furthermore, the biological and behavioral mechanisms underlying these associations are poorly understood. Here, the available evidence on the association of PTSD with CVD from population, basic, and genomic research as well as from clinical and translational research are reviewed, seeking to identify major research gaps, barriers, and opportunities in knowledge acquisition and technology as well as research tools to support and accelerate critical research for near-term and longer-term translational research directions. Large-scale, well-designed prospective studies, capturing diverse and high-risk populations, are warranted that include uniform phenotyping of PTSD as well as broad assessment of biological and behavioral risk factors and CVD outcomes. Available evidence from functional brain imaging studies demonstrates that PTSD pathophysiology includes changes in specific anatomical brain regions and circuits, and studies of immune system function in individuals with PTSD suggest its association with enhanced immune inflammatory activity. However, establishment of animal models and human tissue biobanks is also warranted to elucidate the potential causal connection of PTSD-induced brain changes and/or inflammation with CVD pathophysiology. Emerging large-scale genome-wide association studies of PTSD will provide an opportunity to conduct mendelian randomization studies that test hypotheses regarding the presence, magnitude, and direction of causal associations between PTSD and CVD outcomes. By identifying research gaps in epidemiology and genomics, animal, and human translational research, opportunities to better justify and design future interventional trials are highlighted that may test whether treatment of PTSD or underlying neurobiological or immune dysregulation may improve or prevent CVD risk or outcomes.

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: ß = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: ß = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (ß = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (ß = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (ß = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (ß = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Trauma exposure and stress-related disorders in a large, urban, predominantly African-American, female sample.

The current study investigated the relationship between trauma exposure and psychopathology in a sample of predominately African-American women of low socioeconomic status (SES). Women (N = 7430) were recruited from medical clinics at two large public hospitals in Atlanta, GA, from 2005 to 2017. Women were assessed for sociodemographics, life-course trauma burden, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) utilizing self-report and structured clinical interview assessments. The effects of trauma exposure on current and lifetime PTSD and MDD were examined. Ninety-one percent of women reported trauma exposure, 83% reported a monthly household income of less than $2000, and 41% reported a history of arrest. Regarding psychiatric diagnoses, 30.8% met the criteria for probable MDD, and 32.3% met the criteria for probable PTSD. History of childhood abuse and total lifetime trauma significantly increased PTSD and depressive symptoms with additional incremental trauma exposure. PTSD and depressive symptom scores (95% CI) increased from 5.5 (5.0-6.1) and 8.4 (7.9-9.0) in the no trauma group to 20.8 (20.1-21.5) and 20.4 (19.7-21.2), respectively, in those exposed to four or more types of trauma. These results show high rates of adult and childhood trauma exposure, PTSD, MDD, and an additive effect of lifetime trauma exposure on the development of PTSD and MDD in a sample of low SES African-American women. These findings bring light to the high psychiatric symptom burden in this population and call for increased availability of interventions to address symptoms as well as policies aimed at reducing trauma exposure across the lifespan.

Adverse childhood experiences in African Americans: Framework, practice, and policy.

Adverse childhood experiences (ACEs) disproportionately impact African Americans because of profound subjection to historical-systemic oppression in addition to personal and intergenerational trauma exposure. This article utilizes a biopsychosocial-cultural framework to understand the correlates of ACE exposure in African Americans and attends to the cultural factors that contribute to resilience. We review the evidence base for culturally informed, preventive-interventions, as well as strategies for bolstering this work by capitalizing on cultural strengths that are salient in the African American community. We also highlight pertinent policy initiatives guided by recent strategic outlines by the Centers for Disease Control and Prevention. These policies provide the backdrop for the recommendations offered to facilitate the healthy biopsychosocial development of individuals and families. These recommendations can contribute to the expansion and creation of new policies that aim to strengthen individual coping in the face of adversity, enhance family bonds and resilience, and promote community capacity to reduce ACE exposure in African Americans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Polygenic risk scores differentiate schizophrenia patients with toxoplasma gondii compared to toxoplasma seronegative patients.

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex. Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R2 = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R2 (R2 = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was <0.05 for SCZ-PRS 55% of the time but was rarely (6% of the time) comparable to the high p-value of the seropositive group at p > 0.354. We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.

The renin-angiotensin system in PTSD: a replication and extension.

Prior observational studies have suggested that medications targeting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs), may be associated with decreased PTSD symptoms. Given known sex differences in PTSD prevalence and cardiovascular disease, here we tested whether the effects of ACE-I/ARB status on PTSD differ by sex. We also expanded these observations with replication analyses in a large biorepository database. Participants in the initial sample included 840 trauma-exposed individuals recruited as part of the Grady Trauma Project. The Modified PTSD Symptom Scale (M-PSS) was administered and ACE-I/ARB status was determined by self-report. Replication analyses were conducted using a large biorepository database (Partners Healthcare Biobank, N = 116,389) with diagnoses and medication status based on available electronic health records. Among individuals treated with ACE-Is/ARBs in the initial sample, women had significantly higher M-PSS total and Re-experiencing severity compared to men (p's < 0.05). Analyses with the large biorepository sample robustly replicated the overall effects of ACE-I/ARB medication associated with lower rate of PTSD diagnosis (p < 0.001). We also demonstrated that this effect may be specific to the renin-angiotensin system as it did not replicate for beta-blockers, calcium channel blockers, or diuretics. When we examined more specific drug classes, results indicated that the ACE-I/ARB effect on PTSD may be driven more by ARBs (e.g., Losartan) than by ACE-Is. Post-hoc analyses indicated that racial differences may exist in these effects. Overall, our results replicate and extend prior observations that the renin-angiotensin system is associated with PTSD. Medications targeting this system may be worthy of further investigation for PTSD treatment. Our findings suggest that sex and race effects should be considered in future treatment research.

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

Diet, Stress and Mental Health.

INTRODUCTION: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. METHODS: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. RESULTS: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. CONCLUSIONS: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.

Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex.

Dysregulated fear conditioned responses have been associated with PTSD in adults, with increased fear-potentiated startle (FPS) serving as a potential intermediate phenotype for PTSD risk. This phenotype has also been associated with stress-related ADCYAP1R1 gene variants in adult women. However, FPS and genotype have not yet been examined during development. The aim of this study was to examine developmental changes in fear conditioning, and to see whether these changes were impacted by genotype and trauma. Differential fear conditioning using FPS was tested in n = 63 children ages 8-13 at two visits (V1, V2) 1 year apart. Startle response was measured using electromyograph recordings of the eyeblink muscle. The rs2267735 SNP of the ADCYAP1R1 gene was extracted from genome-wide (GWAS) analyses. Trauma exposure was assessed using the Violence Exposure Scale-Revised (VEX-R). We found significant Visit by Genotype interactions, with CC genotype increasing FPS from V1 to V2. At V2 there was a Genotype by Violence interaction, with higher FPS in the CC vs G allele groups among those with higher violence exposure (F = 17.46, p = 0.0002). Females with the CC genotype had higher FPS compared to G allele females (F = 12.09, p = 0.002); there were no effects of genotype in males. This study showed Gene × Environment × Development and Gene × Sex effects of ADCYAP1R1 in a high-risk pediatric population. Those with the CC genotype and high levels of violence exposure, as well as females with the CC genotype, showed the greatest conditioned fear responses in adolescence.

Evaluating the impact of trauma and PTSD on epigenetic prediction of lifespan and neural integrity.

Post-traumatic stress disorder (PTSD) is a debilitating disorder that develops in some people following trauma exposure. Trauma and PTSD have been associated with accelerated cellular aging. This study evaluated the effect of trauma and PTSD on accelerated GrimAge, an epigenetic predictor of lifespan, in traumatized civilians. This study included 218 individuals with current PTSD, 427 trauma-exposed controls without any history of PTSD and 209 subjects with lifetime PTSD history who are not categorized as current PTSD cases. The Traumatic Events Inventory (TEI) and Clinician-Administered PTSD Scale (CAPS) were used to measure lifetime trauma burden and PTSD, respectively. DNA from whole blood was interrogated using the MethylationEPIC or HumanMethylation450 BeadChips. GrimAge estimates were calculated using the methylation age calculator. Cortical thickness of 69 female subjects was assessed by using T1-weighted structural MRI images. Associations between trauma exposure, PTSD, cortical thickness, and GrimAge acceleration were tested with multiple regression models. Lifetime trauma burden (p = 0.03), current PTSD (p = 0.02) and lifetime PTSD (p = 0.005) were associated with GrimAge acceleration, indicative of a shorter predicted lifespan. The association with lifetime PTSD was replicated in an independent cohort (p = 0.04). In the MRI sub sample, GrimAge acceleration also associated with cortical atrophy in the right lateral orbitofrontal cortex (padj = 0.03) and right posterior cingulate (padj = 0.04), brain areas associated with emotion-regulation and threat-regulation. Our findings suggest that lifetime trauma and PTSD may contribute to a higher epigenetic-based mortality risk. We also demonstrate a relationship between cortical atrophy in PTSD-relevant brain regions and shorter predicted lifespan.