Polygenic Risk for Externalizing Psychopathology and Executive Dysfunction in Trauma-Exposed Veterans

Abstract

The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans (n =537, n =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes. As hypothesized, polygenic risk positively predicted externalizing psychopathology and negatively predicted performance on inhibitory control tasks. Gene-by-environment effects were also evident, with trauma exposure predicting greater impulsivity and less working memory capacity, but only at high levels of genetic liability. As expected, polygenic risk was not associated with internalizing psychopathology or episodic memory performance. This is the first independent replication of the polygenic score as a measure of genetic predispositions for externalizing and provides preliminary evidence that executive dysfunction is a heritable vulnerability for externalizing psychopathology.

Keywords: genes; impulsivity; inhibitory control; internalizing; veterans; working memory.

Figure 1. Polygenic Risk Score Associations with Externalizing and Internalizing Psychopathology

Structural equation model of polygenic risk score predicting externalizing and internalizing latent variables. ASPD = antisocial personality disorder. ALC= alcohol abuse/dependence. CAN = cannabis abuse/dependence. COC = cocaine abuse/dependence. MDE = major depressive episode. DYS = dysthymia. PANIC = panic disorder. AGOR = agoraphobia. PHOBIA = specific phobia. OCD = obsessive-compulsive disorder. GAD = generalized anxiety disorder. PTSD = posttraumatic stress disorder. Paths for age, sex, and ancestry principal components were included in the model, but are not depicted. RMSEA = .06; SRMR = .06; CFI = .80. Significant standardized parameter estimates depicted in bold (p < .05).

Figure 2. Polygenic Risk x Lifetime Trauma Exposure Predicts Impulsive Personality Traits

Correlations between impulsive personality traits on the Multidimensional Personality Questionnaire-Brief and lifetime trauma exposure as a function of polygenic risk score liability. Lifetime trauma exposure predicted greater impulsive traits as polygenic risk load increased. Bars represent partial correlations accounting for age, sex, and ancestry principal components. N = 151. Polygenic Risk Score: Low n = 50, Moderate n = 50, High n = 51. *p < .05. **p < .01.

Figure 3. Polygenic Risk x Lifetime Trauma Exposure Predicts Working Memory Performance

Lifetime trauma exposure predicting working memory performance as a function of polygenic risk. To decompose the interaction, polygenic risk score was grouped into low, moderate, and high categories reflecting tertiles. N = 182. Polygenic Risk Score: Low n = 60, Moderate n = 59, High n = 63.