Trauma related drinking to cope: A phenotypic and molecular genetic investigation of the self-medication model

Posttraumatic stress disorder (PTSD) and alcohol use problems (AUP) commonly co-occur, have shared latent genetic risk, and are associated with many negative public health outcomes. Via a self-medication framework, trauma-related drinking to cope (TRD), an unexplored construct to date, may help explain why these two disorders co-occur, thus serving as an essential target for treatment and prevention efforts. The present study aimed to create a novel measure of TRD and examine its psychometric properties, investigate its indirect influences on the association between PTSD and AUP, as well as explore its potential shared molecular genetic risk with PTSD in a genetically-informative study of college students. A sample of 1,896 students with a history of trauma and alcohol use provided genotypic data and completed an online assessment battery. First, the psychometric properties of TRD and how it relates to relevant constructs were examined using descriptive statistics and structural equation modeling. Findings demonstrated support for the external validation of TRD, both with regard to PTSD and alcohol consumption and related problems, and suggested that TRD is a more specific measure of drinking to cope motives compared to the commonly used Drinking Motives Questionnaire coping subscale. Second, results from a correlated multiple mediator model indicated that, while accounting for the effects of generalized drinking motives, TRD partially mediated the relation between PTSD and AUP and that this relationship was stronger for males than for females. Results were substantiated using longitudinal data. Third, univariate and bivariate genotypic analyses were conducted for TRD and PTSD, most of which resulted in null findings likely due to insufficient sample sizes. However, genome wide association analysis identified several significant genetic variants associated with TRD in participants of European Ancestry. Genes associated with TRD included PRAME, a protein coding gene with antithetical effects to genes commonly implicated in alcohol metabolism, as well as several genes implicated in immune system functioning (e.g., IGH, IGHE, ELK2AP). Polygenic risk for PTSD was associated with PTSD in the present sample and nominally associated with TRD. Findings are discussed in the context of limitations, clinical implications, and future directions

EXAMINATION OF BASAL NEUROENDOCRINE LEVELS IN OIF/OEF/OND VETERANS

Abstract EXAMINATION OF BASAL NEUROENDOCRINE LEVELS IN OIF/OEF/OND VETERANS By Sage E. Hawn, B.S. A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2015. Major Director: Ananda B. Amstadter, PhD. Associate Professor Departments of Psychiatry, Psychology, & Human and Molecular Genetics High rates of combat exposure exist among veterans of the recent conflicts, and are associated with debilitating mental health conditions, including posttraumatic stress disorder (PTSD). Numerous psychosocial and biologic factors are associated with PTSD, including the HPA-axis. The present study aimed to compare baseline neuroendocrine levels by trauma group (PTSD, trauma exposed [TE], and non-trauma controls [NTC]) among a sample of young veterans. An exploratory aim was to examine potential moderators of the relation between PTSD and basal cortisol/ACTH. Group differences in cortisol were nominally significant, with the NTC group having significantly higher cortisol than the PTSD group. Sleep disturbance was the only moderator of this relationship in cortisol, although lifetime trauma load significantly predicted basal cortisol across all models. No significant effects were demonstrated for ACTH. Examining effects of trauma on basal physiology provides a critical stepping ground for future investigations that may inform targeted prevention and intervention efforts

Evaluation of a new trauma-related drinking to cope measure: Latent structure and heritability

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur, share latent genetic risk, and are associated with many negative public health outcomes. Via a self-medication framework, trauma-related drinking to cope (TRD), an unexplored phenotype to date, may help explain why these two disorders co-occur, thus serving as an essential target for treatment and prevention efforts. This study sought to create a novel measure of TRD and to investigate its indirect influences on the association between PTSD and AUD, as well as its potential shared molecular genetic risk with PTSD in a genetically-informative study of college students. A sample of 1,896 undergraduate students with a history of trauma and alcohol use provided genotypic data and completed an online assessment battery. The psychometric properties of TRD and how it relates to relevant constructs were examined using descriptive statistics and structural equation modeling. Results of a correlated multiple mediator model indicated that, while accounting for the effects of generalized drinking motives, TRD partially mediated the relation between PTSD and alcohol use problems (β = 0.213, p \u3c .001), consistent with the self-medication hypothesis, and that this relationship was stronger for males (β = 0.804, p \u3c .001) than for females (β = 0.463, p \u3c .001). Results were substantiated using longitudinal data. Genotypic analyses to be presented will include univariate genome wide complex trait analyses (GCTA) to establish SNP-based heritability associated with TRD and PTSD, separately, as well as bivariate GCTA to examine potential overlap in heritability between TRD and PTSD.https://scholarscompass.vcu.edu/gradposters/1047/thumbnail.jp

THE ASSOCIATIONS BETWEEN SEXUAL VICTIMIZATION AND HEALTH OUTCOMES AMONG LGBQA COLLEGE STUDENTS: EXAMINING THE MODERATING ROLE OF SOCIAL SUPPORT

Sexual victimization is a prevailing public health concern that differentially impacts sexual minority populations (i.e., people who identify as lesbian, gay, bisexual, asexual, or queer) compared with their heterosexual and cisgender counterparts (McCauley et al., 2018). Studies have shown that sexual violence is associated with depressive symptoms, post-traumatic stress disorder symptoms, and alcohol use (Aosved et al., 2011; Bedard-Gilligan et al, 2011; Carey et al., 2018) among heterosexual college students. However, we know less about the potential effects of sexual victimization on health outcomes among sexual minority college students. Understanding these relations are especially important because sexual minority college students often experience unique challenges and are at increased risk of sexual victimization in comparison to their counterparts (Cantor et al., 2015; Edwards et al., 2015). Moreover, few studies to date have examined the moderating role of social support in buffering the links between sexual victimization and health outcomes. Guided by the minority stress framework (Meyer, 2003), the current study examined the extent to which sexual victimization influences health outcomes (i.e., depressive symptoms, post-traumatic stress disorder symptoms, and alcohol use disorder) among sexual minority college students. Furthermore, we examined whether social support moderated the association between sexual victimization and each health outcome. The current study included 234 students who identified as being part of the Queer community (e.g., Gay, Lesbian, Asexual, and Queer) from a larger university-wide study (i.e., Spit for Science; Dick et al., 2014). The participants in the present study were 18-22 years old (M = 18.46, SD = .412) and majority female (i.e., 74%). Fifty-six percent of the participants self- identified as White, 16% as Black or African American, 13% as Asian, and 15% as American Indian, Latinx, Pacific Islander, or Multiracial. Students provided online self-reports of their sexual victimization experiences (Blake et al., 1990), social support (Hays et al., 1995), depressive symptoms (Derogatis et al., 1973), post-traumatic stress disorder symptoms (Weathers et al., 2013) and alcohol use (DSM-V). We used a series of regression models in Mplus v 7.2 (Muthén & Muthén, 1998–2014) to test our research questions, with multiple imputation to handle missing data. Findings indicated that sexual victimization was positively related to depressive symptoms (b = .21, p = .00), post- traumatic stress disorder symptoms (b = .43, p = .00), and alcohol use disorder (b = .45, p = .00). Furthermore, social support significantly moderated the association between sexual victimization and depressive symptoms, however, in a direction contrary to hypotheses. Specifically, greater sexual victimization was associated with greater depressive symptoms among sexual minority college students with higher levels of social support (b = .29, p = .00), and the association was not significant for sexual minority college students with lower levels of social support (b = .13, p = .26; Figure 1). Discussion will center on the detrimental effects of sexual victimization on health outcomes among sexual minority college students, as well as providing potential explanations and future directions for the nuanced ways social support functions in the lives of sexual minority college students.https://scholarscompass.vcu.edu/gradposters/1079/thumbnail.jp

Stress reactivity to an electronic version of the Trier Social Stress Test: a pilot study

Social stressors that rely on the inclusion of confederates (i.e., Trier Social Stress Test, TSST) are often used in clinical laboratory research paradigms to elicit a measurable stress response in participants. Although effective, the TSST is labor intensive and may introduce error variance as a function of confederate race, gender, and/or response characteristics. The present study aimed to develop and validate an electronic version of the TSST (e-TSST). The primary aim was to compare the e-TSST to an e-neutral control condition; the exploratory aim was to compare the magnitude of stress response elicited by the e-TSST to that elicited by the traditional TSST. Forty-three healthy adults were randomized to the e-TSST or e-neutral condition. Subjective (participant-rated distress) and objective [cortisol, heart rate (HR), and blood pressure] indices of stress were collected prior to, and multiple times following, the stressor. Using archival data collected from 19 healthy participants exposed to the traditional TSST in a prior study, stress reactivity was compared between the electronic and traditional versions of the TSST. The e-TSST elicited significant increases in all measures of stress reactivity compared to the e-neutral condition, with the exception of HR. Results showed that the magnitude of subjective distress, BP, and HR responses elicited by the e-TSST did not differ significantly from that elicited by the traditional TSST. The traditional TSST elicited significantly higher cortisol than the e-TSST. Although these findings provide initial support for the development of electronic versions of the TSST, further refinement of the e-TSST is warranted prior to broad adoption of this technology. A refined, reliable e-TSST could allow for increased utilization of the TSST by enhancing convenience, reducing labor costs, and limiting potential error variance introduced by human confederates

An EWAS of Dementia Biomarkers and Their Associations with Age, African Ancestry, and PTSD

Background Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aβ40, Aβ42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers. Methods Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aβ40 and Aβ42, Factor A and the second factor, defined by GFAP, NfL and pTau-181, Factor TN. Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations. Results The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (β = 0.581, p \u3c 0.001) than Factor A (β = 0.330, p \u3c 0.001). Genotype-determined African ancestry was associated with lower Factor A (β = 0.196, p \u3c 0.001). Contrary to our primary hypothesis, we found a modest negative bivariate correlation between PTSD and the TN factor scores (r = - 0.133, p \u3c 0.001) attributable primarily to reduced levels of GFAP (r = - 0.128, p \u3c 0.001). Conclusions This study identified novel epigenetic associations with ATN biomarkers and demonstrated robust age and ancestral associations that will be essential to consider in future efforts to develop the clinical applications of these tests. The association between PTSD and reduced GFAP, which has been reported previously, warrants further investigation

Trauma Exposure and Transdiagnostic Distress: Examining Shared and PTSD-Specific Associations

Dimensional models of psychopathology suggest that the causes and consequences of psychopathology are attributable to a combination of syndrome specific and transdiagnostic features. There is considerable evidence that trauma exposure confers risk for a wide range of psychiatric conditions, yet no previous work has specifically examined the higher-order effects of trauma exposure within a structural model. We examined transdiagnostic and PTSD-specific associations with multiple forms of trauma exposure within a nation-wide sample (N = 1,649; 50% female) of military Veterans over-selected for posttraumatic stress disorder (PTSD). A higher-order Distress variable was estimated using PTSD, major depressive disorder (MDD), and generalized anxiety disorder (GAD) symptoms as indicators. A structural equation model spanning three measurement time points over an average of 3.85 years was then used to examine the unique roles of higher-order Distress and PTSD residual variance in accounting for the relations between trauma exposure and psychosocial impairment. Results suggest that the association between trauma exposure and PTSD symptoms is primarily mediated by higher-order Distress, but that PTSD severity does have a significant association with trauma exposure independent of Distress. Both higher-order Distress and PTSD-specific variance were necessary to account for the association between trauma exposure and future functional impairment. This work suggests there may be shared etiology linking cumulative trauma exposure and a range of internalizing symptoms. Continued application of higher-order dimensional models is needed to provide a more comprehensive understanding of the consequences of trauma exposure

PTSD and Alcohol Use Disorders Predict the Pace of Cellular Aging

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression. Results showed that PTSD (β = .199) and AUD (β = .186) were associated with a quickened pace of epigenetic aging over time (ps \u3c .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology

For Whom the Bell Tolls: Psychopathological and Neurobiological Correlates of the DNA Methylation Index of Time-To-Death

Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge (“GrimAge residuals”), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps \u3c 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj \u3c 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj \u3c 0.001; IL-6: padj \u3c 0.001), and immune functioning (padj \u3c 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj \u3c 0.001; TNF-α: padj \u3c 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment

Trauma Exposure and Transdiagnostic Distress: Examining Shared and PTSD-Specific Associations

Dimensional models of psychopathology suggest that the causes and consequences of psychopathology are attributable to a combination of syndrome specific and transdiagnostic features. There is considerable evidence that trauma exposure confers risk for a wide range of psychiatric conditions, yet no previous work has specifically examined the higher-order effects of trauma exposure within a structural model. We examined transdiagnostic and PTSD-specific associations with multiple forms of trauma exposure within a nation-wide sample (N = 1,649; 50% female) of military Veterans over-selected for posttraumatic stress disorder (PTSD). A higher-order Distress variable was estimated using PTSD, major depressive disorder (MDD), and generalized anxiety disorder (GAD) symptoms as indicators. A structural equation model spanning three measurement time points over an average of 3.85 years was then used to examine the unique roles of higher-order Distress and PTSD residual variance in accounting for the relations between trauma exposure and psychosocial impairment. Results suggest that the association between trauma exposure and PTSD symptoms is primarily mediated by higher-order Distress, but that PTSD severity does have a significant association with trauma exposure independent of Distress. Both higher-order Distress and PTSD-specific variance were necessary to account for the association between trauma exposure and future functional impairment. This work suggests there may be shared etiology linking cumulative trauma exposure and a range of internalizing symptoms. Continued application of higher-order dimensional models is needed to provide a more comprehensive understanding of the consequences of trauma exposure