Mackenzie J. Lind

The genetics and epigenetics of PTSD: overview, recent advances, and future directions

This paper provides a brief summary and commentary on the growing literature and current developments related to the genetic underpinnings of posttraumatic stress disorder (PTSD). We first briefly provide an overview of the behavioral genetic literature on PTSD, followed by a short synopsis of the substantial candidate gene literature with a focus on genes that have been meta-analyzed. We then discuss the genome-wide association studies (GWAS) that have been conducted, followed by an introduction to other molecular platforms used in PTSD genomic studies, such as epigenetic and expression approaches. We close with a discussion of developments in the field that include the creation of the PTSD workgroup of the Psychiatric Genomics Consortium, statistical advances that can be applied to GWAS data to answer questions of heritability and genetic overlap across phenotypes, and bioinformatics techniques such as gene pathway analyses which will further advance our understanding of the etiology of PTSD.

An Epidemiologic Study of Childhood Sexual Abuse and Adult Sleep Disturbances.

Childhood sexual abuse (CSA) is linked to negative consequences, including insomnia. Few studies have examined the enduring effects of CSA on adult insomnia. Given the relationship between sleep and poor health, a better understanding of these effects has clinical implications. We used a representative adult twin sample. Both sexes were assessed with a broad CSA variable, with a subset of females (n = 424) given additional items capturing escalating physical contact and abuse characteristics. A sum score of past-month insomnia symptoms was calculated from the Symptom Checklist-90 (shortened version). Logistic regression was used to estimate the effects of CSA, physical contact, and incident characteristics on insomnia symptoms. Of the full sample (N = 8,184), 9.8% reported CSA. CSA significantly predicted insomnia symptoms in the female sample (n = 1,407; odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.35-2.06, p < .0001) but the continuum of physical contact did not. Individually, more than 1 perpetrator and feeling forced/threatened increased sleep risk, whereas having a male perpetrator (vs. female or multiple) decreased risk. These associations did not hold when combined. In the mixed-sex sample (n = 6,777), we replicated our CSA finding (OR = 1.65, 95% CI = 1.34-2.04, p < .0001) and found that female gender (OR = 1.16, 95% CI = 1.03-1.30, p = .0125), but not the gender*CSA interaction, was significant. CSA predicts adult insomnia symptoms decades after abuse, but the small sample size for incident characteristics (n = 424) resulted in limited conclusions about associated risk.

A Longitudinal Twin Study of Insomnia Symptoms in Adults

OBJECTIVE Twin modeling was used to conduct a genetically informative longitudinal analysis of insomnia symptoms in both sexes. METHOD Data from the Virginia Adult Twin Studies of Psychiatric and Substance Use Disorders (n = 7,500) were used. Past-month insomnia symptoms were assessed at two time points with the shortened version of the Symptom Checklist-90. A composite score for the insomnia items (trouble falling asleep, restless or disturbed sleep, early morning awakenings) was computed. Twin modeling on the composite score was conducted in OpenMx to decompose the phenotypic variance, to examine the longitudinal stability of etiologic influences on insomnia symptoms, and to test for sex differences. RESULTS Insomnia symptoms were most commonly endorsed at a mild severity level (composite score mean = 2.24, standard deviation = 2.51). There was no evidence for sex effects in either of the univariate models, and insomnia symptoms were found to be modestly heritable (~25% at Time 1 and ~22% at Time 2). In the longitudinal measurement model, which accounts for error of measurement, the heritability for the latent factor of insomnia symptoms increased substantially, and demonstrated quantitative sex differences. The heritability of the latent insomnia factor was ~59% in females and ~38% in males. CONCLUSIONS Genetic factors influence insomnia symptoms in adults, moreso for females than males, and these influences are largely stable over time. When taking into account measurement error, heritability estimates are substantial, but unique environmental factors continue to account for a large amount of variance in insomnia symptoms.

The impact of resilience and subsequent stressful life events on MDD and GAD

There remains a dearth of research examining the “buffering” effect of resilience, wherein resilience at one point in time would be expected to protect an individual against development of psychopathology following future adverse life events.

Does Parenting Influence the Enduring Impact of Severe Childhood Sexual Abuse on Psychiatric Resilience in Adulthood

This study examined the effect of parenting on the association between childhood sexual abuse (CSA) and psychiatric resilience in adulthood in a large female twin sample (n = 1423) assessed for severe CSA (i.e., attempted or completed intercourse before age 16). Severe CSA was associated with lower resilience to recent stressors in adulthood (defined as the difference between their internalizing symptoms and their predicted level of symptoms based on cumulative exposure to stressful life events). Subscales of the Parental Bonding Instrument were significantly associated with resilience. Specifically, parental warmth was associated with increased resilience while parental protectiveness was associated with decreased resilience. The interaction between severe CSA and parental authoritarianism was significant, such that individuals with CSA history and higher authoritarianism scores had lower resilience. Results suggest that CSA assessment remains important for therapeutic work in adulthood and that addressing parenting may be useful for interventions in children with a CSA history.

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta-Analysis: Meta-Analysis of ADCYAP1R1 Polymorphism and PTSD

Recent studies point to the potential role of the (pituitary) adenylate cyclase activating polypeptide receptor 1 (ADCYAP1R1) gene, which has been implicated in stress response, in posttraumatic stress disorder (PTSD). Multiple genetic association studies have examined potential PTSD risk related to this gene, with mixed results. We conducted a meta-analysis of rs2267735 in ADCYAP1R1 in PTSD. A literature search was conducted using PubMed and PsycINFO, resulting in nine studies that met criteria for inclusion in analysis. Biostats Comprehensive Meta-Analysis was used to conduct the main meta-analysis on the combined sex sample, as well as two subanalyses examining effects separately in female and male participants. Results indicated that the C allele of rs2267735 conferred significant risk for PTSD in the combined sex data, OR = 1.210, 95% CI [1.007, 1.454], p = .042, and in the subsample of women and girls, OR = 1.328, 95% CI [1.026, 1.719], p = .031; but not in the subsample of men and boys, OR = 0.964, 95% CI [0.733, 1.269], p = .796. These results provide evidence for an association between ADCYAP1R1 and PTSD and indicate that there may indeed be sex differences. Implications of these findings, including the role of rs2267735 as one modulator of the stress system, are discussed.

Sleep Disturbances in OEF/OIF/OND Veterans: Associations with PTSD, Personality, and Coping.

STUDY OBJECTIVES Sleep disturbances are well documented in relation to trauma exposure and posttraumatic stress disorder (PTSD), but correlates of such disturbances remain understudied in veteran populations. We conducted a preliminary study of sleep disturbances in Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn veterans (n = 133; mean [standard deviation] age = 29.8 [4.7] y). METHODS Veterans were assigned to one of three groups based on responses to the Clinician Administered PTSD Scale: control (no trauma-exposure [TE] or PTSD), TE, and PTSD. Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Measures of resilience, trauma load, personality, coping, alcohol use, and mild traumatic brain injury were also assessed via self-report. RESULTS The PTSD group had significantly more disturbed sleep (PSQI global score mean = 8.94, standard deviation = 3.12) than control (mean = 5.27, standard deviation = 3.23) and TE (mean = 5.34, standard deviation = 3.17) groups, but there were no differences between TE and control. The same pattern emerged across most PSQI subscales. Results of linear regression analyses indicated that current smoking, Army (versus other military branches), neuroticism, and using substances to cope were all significant correlates of higher sleep disturbance, whereas post-deployment social support was associated with less sleep disturbance. However, when combined together into a model with PTSD status, only neuroticism and substance use coping remained significant as predictors of more disturbed sleep. CONCLUSIONS These initial findings suggest that TE itself may not be an independent risk factor for disturbed sleep in veterans, and that neurotic personality and a tendency to cope by using substances may partially explain sleep disturbance, above and beyond a diagnosis of PTSD.

GxE effects of FKBP5 and traumatic life events on PTSD: A meta-analysis

BACKGROUND Twin studies have demonstrated that both genetic and environmental factors influence risk for posttraumatic stress disorder (PTSD), and there is some evidence supporting the interplay of genes and environment (GxE). Many GxE studies within the PTSD literature have focused on genes implicated in the stress response system, such as FK506 binding protein 51 (FKBP5). Given inconsistencies across GxE literature as a whole, a meta-analysis to synthesize results is warranted. METHODS Studies were identified through PubMed and PsycINFO. A meta-analysis was conducted using a random effects model in the MAc package in R. Heterogeneity of the effect size distribution was examined with Cochrans Q statistic. A Simes procedure was used to test the gene-level GxE effect for FKBP5 interacting with trauma. RESULTS A significant gene-level GxE gene effect was demonstrated for FKBP5 when pooled across all four examined variants (rs1360780, rs3800373, rs9296158, rs9470080) when interacting with trauma exposure on PTSD. Significant large GxE effect sizes were also found for each independent variant. There was no evidence for heterogeneity of variance. LIMITATIONS Limitations include reduced power for detecting variability across moderators, potential bias due to failure of meta-analyzed studies to account for two-way covariate x gene and covariate x environment influences, and a high false discovery rate that is characteristic of GxE analyses. CONCLUSIONS This is the first study to quantify an overall gene-level effect of FKBP5 in a GxE analysis of PTSD, evidence which may be used to address current issues in the FKBP5 GxE literature (e.g., disparate variants, low sample sizes and power), as well as inform follow-up functional research.

Genetics of Post-traumatic Stress Disorder and Sleep Disturbance

We will begin by providing a brief summary of the sleep and post-traumatic stress disorder (PTSD) literature in veterans, followed by an overview of common genetic methods utilized across studies. Next, we will provide a summary of the vast PTSD genetic literature, followed by a review of the sleep genetic literature with a focus on insomnia and related sleep symptoms. Although there are no molecular genetic studies to date examining the overlap between sleep and PTSD, we compare the literature with a focus on hypothesized genes that may contribute to the comorbidity of these conditions. The chapter will finish with a summary of key gaps in the literature and future directions that can address these concerns.

Relation between coping and posttrauma cognitions on PTSD in a combat-trauma population

ABSTRACT Individual differences in cognitive processes and coping behaviors play a role in the development and maintenance of posttraumatic stress disorder (PTSD). Given the large numbers of combat-exposed service members returning from the Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) conflicts, exploring individual differences in cognitive-affective processes is important for informing our understanding of PTSD etiology and early intervention in military samples. The present study examined the unique main and interactive effects of negative posttrauma cognitions (i.e., negative beliefs about self [NS], the world [NW], and self-blame [SB]) and coping strategies (i.e., positive behavioral, positive cognitive, avoidant coping, and social and emotional coping) on PTSD diagnosis within 155 (Mage = 30.7, SD = 4.48) OEF/OIF/OND combat trauma-exposed Veterans recruited from an ongoing study examining the effects of combat trauma and stress reactivity. In the final, stepwise logistic regression analysis, avoidant coping, but no other coping strategy, was significantly positively related to PTSD diagnosis in the initial step. Higher levels of NS, but not NW, were significantly associated with having a PTSD diagnosis, whereas SB was associated with decreased likelihood of PTSD, above and beyond coping strategies. A significant interaction effect was found between NS and positive cognitive coping, such that greater positive cognitive coping weakened the relationship between NS and PTSD. Examining and addressing coping behaviors and negative thoughts of self jointly may benefit assessment and intervention approaches in a combat-trauma population.