Person:

Ressler, Kerry

Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm, or happiness. Positive affect is associated with favorable psychological, physical, and economic outcomes in many longitudinal studies. With a heritability of ≤64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study (GWAS) of positive affect in African American participants, we identify a single nucleotide polymorphism (SNP), rs322931, significantly associated with positive affect at p<5×10−8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli, and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.

Abstract Emotion dysregulation (ED) reflects deficits in understanding and managing negative emotions and may serve as a transdiagnostic mechanism of risk for trauma-related psychiatric disorders. Therefore, understanding neurobiological substrates of ED in traumatized individuals is critical. The present study examined associations between ED and baseline structural differences and patterns of functional activity during an emotional task in a sample of African American women (n = 136) recruited from an urban hospital. Participants engaged in a structural magnetic resonance imaging (MRI) session. A subsample (n = 92) also viewed emotional face stimuli during functional MRI. ED was related to greater dorsal anterior cingulate cortex (dACC) surface area (Pcorr < 0.05) and increased dorsomedial prefrontal cortex (dmPFC) and ventromedial PFC activation to fearful stimuli (Pcorr < 0.05), independent of the trauma and psychiatric symptoms. DMPFC activation was also associated with posttraumatic stress disorder and depression symptoms. Mediation analyses showed a significant mediation effect of ED on the relation between dmPFC activation and psychiatric symptoms. These findings are important since dACC and dmPFC play central roles in fear expression and attention to emotional stimuli. Future longitudinal research is needed to help solidify a model of risk for how such neural substrates may be impacted by traumatic experiences to create ED.

Trauma, especially early life trauma, is a risk factor for the development of both posttraumatic stress disorder and psychosis. The goal of the present study was to determine specific associations between exposure to childhood abuse, PTSD symptoms, and current psychotic disorder. Subjects were recruited from a public, urban hospital (N = 328, >90% African American). Psychotic disorders were measured using the MINI International Neuropsychiatric Interview, PTSD was measured using the Clinician Administered PTSD Scale, child abuse was measured with the Childhood Trauma Questionnaire, and lifetime trauma exposure was measured with the Traumatic Events Inventory. Logistic regression analyses showed that both child abuse and current PTSD were statistically significant predictors of psychotic disorder beyond the effects of lifetime trauma load. When PTSD symptom clusters were examined, avoidance and numbing symptoms showed unique association with psychotic disorder independent of demographic variables and trauma exposure. Using bootstrapping techniques, we found a full indirect effect of PTSD on the association between child abuse and, suggesting a particularly important role of PTSD symptoms in relation to psychotic disorder in the presence of early life trauma. Because this is a cross-sectional study, continued research is needed to determine causality of such models. Identifying co-occurring psychosis and PTSD, particularly in populations with high levels of trauma exposure, is critical and will likely aid in more successful treatment interventions.

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African-American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p < 0.01). Current PTSD was not significantly related to CRP. In a regression model, emotion dysregulation was significantly associated with higher CRP (p < 0.001) independent of body mass index, trauma exposure, and MDD diagnosis. These findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with T2DM, though a causal relationship cannot be determined from this study.

Little is known about how emotion dysregulation (ED) and trauma exposure differentially affect the relationship between abuse in childhood and adult substance use. We examined associations between child abuse, trauma exposure, ED, and current substance use in an already existing dataset. Participants (N = 2,014 adults, 90% African American) had been recruited from an urban hospital for a parent study. Analyses showed that drug and alcohol use was significantly positively correlated with child abuse (emotional, physical, and sexual), later trauma exposure, and ED (all ps < .001). Linear regression showed that exposure to abuse when older than a child was significantly associated with drug and alcohol use independent of child abuse and demographic variables (R 2Δ = .08, p < .001; R 2Δ = .04, p < .001). ED was significantly associated with drug and alcohol use independently of child abuse, nonabuse trauma, and demographic variables (R 2Δ = .02, p < .001; R 2Δ = .04, p < .001). Multiple mediation analyses showed that ED and later trauma exposure accounted for variance in the association between emotional abuse and substance use (p < .001). A better understanding of vulnerabilities to additional traumatization and emotion‐regulation deficits in individuals who have been exposed to child abuse and in addition have comorbid substance use problems may inform treatments that lead to improved outcomes.

Background: The nature and underlying mechanisms of the observed increased vulnerability to posttraumatic stress disorder (PTSD) in women are unclear. Methods: We investigated the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women. The analysis was conducted using female-specific summary statistics from large genome-wide association studies (GWAS) and a cohort of 3577 European American women (966 PTSD cases and 2611 trauma-exposed controls). We applied a high-resolution polygenic score approach and Mendelian randomization analysis to investigate genetic correlations and causal relationships. Results: We observed an inverse association of PTSD with genetically determined anthropometric traits related to body shape, independent of body mass index (BMI). The top association was related to BMI-adjusted waist circumference (WCadj; R = –0.079, P < 0.001, Q = 0.011). We estimated a relative decrease of 64.6% (95% confidence interval = 27.5–82.7) in the risk of PTSD per 1-SD increase in WCadj. MR-Egger regression intercept analysis showed no evidence of pleiotropic effects in this association (Ppleiotropy = 0.979). We also observed associations of genetically determined WCadj with age at first sexual intercourse and number of sexual partners (P = 0.013 and P < 0.001, respectively). Conclusions: There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0491-4) contains supplementary material, which is available to authorized users.