Additive serotonergic genetic sensitivity and cortisol reactivity to lab-based social evaluative stress: Influence of severity across two samples.

Prior work demonstrates that an additive serotonergic multilocus genetic profile score (MGPS) predicts amplified risk for depression following significant life stress, and that it interacts with elevations in the cortisol awakening response to predict depression. The serotonin system and HPA-axis have bidirectional influence, but whether this MGPS predicts acute cortisol reactivity, which might then serve as a mechanism for depression, is unknown. Our prior work suggests that depression risk factors predict blunted cortisol reactivity to explicit negative evaluative lab-based stress. Thus, we hypothesized that a 4-variant serotonergic MGPS (three SNPs from the original 5-variant version plus 5HTTLPR) would predict blunted cortisol reactivity to explicit negative evaluative stress versus a control. In Sample 1, growth curve modeling showed that the MGPS predicted heightened cortisol reactivity (p = 0.0001) in an explicitly negative evaluative Trier Social Stress Test variant (TSST) versus a control condition among non-depressed emerging adults (N = 152; 57% female). In Sample 2, 125 males completed the Socially Evaluative Cold Pressor Test (SECPT), an ambiguously negative evaluative manipulation; findings displayed a similar pattern but did not reach statistical significance (ps.075-.091). A participant-level meta-analysis of the two samples demonstrated a significant effect of negative evaluation severity, such that the MGPS effect size on reactivity increased linearly from control to SECPT to an explicitly negative evaluative TSST. Findings indicate that this MGPS contributes to sensitivity to social threat and that cortisol dysregulation in the context of social stress may be one mechanism by which this MGPS contributes to depression.

Dopaminergic Genetic Variation in Young Adolescents: Associations with Sensation-Seeking.

Deficient reward functioning, including reward-related personality, is implicated in depression's etiology. A dopaminergic genetic multilocus genetic profile score (MGPS) has previously been associated with neural reward responsivity but, despite theoretical basis, has not been studied with reward-related personality. Such research is needed to elucidate associations between genetic variation and reward-related personality in a developmentally sensitive population. In the present study, we examined associations between dopaminergic MGPS's and self-report reward-related personality in two young adolescent samples aged 10-15 years old (Sample 1: N = 100 girls, 82% White, 18% Other; Sample 2: N = 141, 65 girls, 76 boys, 89.36% White, 10.64% Other) using an established MGPS and an augmented MGPS. A "mini" meta-analysis synthesized results across samples. In Sample 1, an exploratory mediation analysis intended to gauge effect size for future work tested a path between the MGPS and depression through significant reward traits. In each independent sample, both MGPS's showed significant associations with sensation-seeking but not social drive, a pattern that persisted following correction. Effect sizes of novel variants were at least as robust as established variants, suggesting their added utility. Additionally, the exploratory mediation analysis suggested no noteworthy indirect effect, but a small (R2 = 0.022), statistically non-significant direct effect of the MGPS predicting prospective depressive symptoms. Results suggest that dopaminergic genetic variation is associated with the reward-related personality trait of sensation seeking but not social drive. Additional work is needed to probe whether sensation seeking may be a path through which this genetic variation confers depression risk.

The cortisol reactivity threshold model: Direction of trait rumination and cortisol reactivity association varies with stressor severity.

Various internalizing risk factors predict, in separate studies, both augmented and reduced cortisol responding to lab-induced stress. Stressor severity appears key: We tested whether heightened trait-like internalizing risk (here, trait rumination) predicts heightened cortisol reactivity under modest objective stress, but conversely predicts reduced reactivity under more robust objective stress. Thus, we hypothesized that trait rumination would interact with a curvilinear (quadratic) function of stress severity to predict cortisol reactivity. Evidence comes from 85 currently non-depressed emerging adults who completed either a non-stressful control protocol (n = 29), an intermediate difficulty Trier Social Stress Test (TSST; n = 26), or a robustly stressful negative evaluative TSST (n = 30). Latent growth curve models evaluated relationships between trait rumination and linear and quadratic effects of stressor severity on the change in cortisol and negative affect over time. Among other findings, a significant Trait Rumination x Quadratic Stress Severity interaction effect for cortisol's Quadratic Trend of Time (i.e., reactivity, B = .125, p = .017) supported the hypothesis. Rumination predicted greater cortisol reactivity to intermediate stress (rp = .400, p = .043), but blunted reactivity to more robust negative evaluative stress (rp = -0.379, p = 0.039). Contrasting hypotheses, negative affective reactivity increased independently of rumination as stressor severity increased (B = .453, p = 0.044). The direction of the relationship between an internalizing risk factor (trait rumination) and cortisol reactivity varies as a function of stressor severity. We propose the Cortisol Reactivity Threshold Model, which may help reconcile several divergent reactivity literatures and has implications for internalizing psychopathology, particularly depression.