Christina M. Sheerin

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.

Variation in SLC1A1 is related to combat-related posttraumatic stress disorder

Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n=418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n=391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR=0.50; OR=1.43). In the linear regression analysis, combat exposure was the only significant predictor (β=0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR=1.15) and severity scores (β=0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system.

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.

Potentially Traumatic Events, Posttraumatic Stress Disorder, and Depression among Adults in Puerto Rico.

The aims of the current study were to examine the prevalence of potentially traumatic events (PTEs), posttraumatic stress disorder (PTSD; data available in males only), and depressive symptoms in a Puerto Rican sample of 678 adult caretakers (50% female) of twins participating in the Puerto Rican Infant Twin Study. The World Health Organization Composite International Diagnostic Interview version 3.0 (CIDI 3.0) was utilized to assess rates of PTEs, PTSD, and depression among male participants while an abbreviated version of the CIDI 3.0 and the Mood and Feelings Questionnaire were administered to females to assess PTEs and depressive symptoms. Significantly more males than females reported exposure to a PTE (76.6% vs. 44.2%, χ2 = 64.44, p < 0.001). In males, endorsement of multiple PTEs was associated with increased level of PTSD symptomatology (β = 0.33, p < 0.001). With regard to depression, a similar dose-response relationship was found in both males and females, with depressive symptoms increasing as number of PTEs increased (βs = 0.15, 0.16, ps < 0.05). Exposure to an attack with a weapon was significantly associated with increased depression symptoms in both males and females (βs = 0.24, 0.20, ps < 0.01, respectively). These findings highlight the need for identification of putative risk and resilience factors among PTE-exposed individuals in Puerto Rico.

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.

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.

Moderation of improvement in self-efficacy following group psychotherapy for PTSD.

Posttraumatic stress disorder (PTSD) is a primary mental health concern of veterans. In clinical settings, efforts to improve broad facets beyond symptom amelioration and consideration of moderators of treatment effectiveness in this population are needed for continued improvement in care. General self-efficacy (GSE) has been indicated as a useful treatment target because of its association with positive outcomes such as increased positive health behaviors. Both race and educational attainment represent potential moderators of treatment response that are relevant for a veteran PTSD population. This study aimed to determine whether a PTSD Recovery Group Therapy Program resulted in improvement in GSE and whether racial and educational differences moderated GSE outcomes. Archival data were examined from male veterans (N = 450) receiving mental health services at a Veterans Affairs medical center using multilevel modeling to examine change in GSE over the course of treatment as well as moderation of change in GSE as a function of race and educational attainment. After completion of group therapy, results indicated there was significant improvement in GSE, with significantly different improvement based on education. Higher levels of education were associated with greater increases in GSE after treatment. Improvement in GSE did not differ by participant race. In clinical settings, efforts to increase GSE and attending to moderators such as educational attainment may be useful for improving PTSD treatment approaches. (PsycINFO Database Record

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.

Effect of expressive and neutral writing on respiratory sinus arrhythmia response over time

BACKGROUND AND OBJECTIVES Parasympathetic activity, as indexed by respiratory sinus arrhythmia (RSA), underlies key aspects of emotional and cognitive self-regulation. Examining time-varying RSA response during expressive writing about trauma may help inform theory about mechanisms of this intervention. The present study investigated changes in RSA during expressive writing. METHODS Participants (N = 246, Mage = 21.5 years, 72% female) were randomly assigned to expressive or neutral writing conditions and wrote for three 20-min sessions. RSA was measured continuously during the first and third writing session. RESULTS Linear mixed model analyses of RSA changes within and across sessions by writing groups found that neutral writers, but not expressive writers, exhibited change in RSA. The overall RSA changes during expressive and neutral writing are consistent with theory about the relationship between cognitive and emotional processing mechanisms and vagal activation. LIMITATIONS As the present study was not a clinical sample selected on trauma exposure, findings should be considered preliminary. Additionally, engagement of affective and cognitive processes was only hypothesized, as manipulation checks were not performed. CONCLUSIONS The present study illustrates the benefits of examining changes in RSA over time. Future work with clinical samples should include additional measures and tasks to better define these mechanisms and rule out alternative hypotheses.