HPA-axis multilocus genetic interaction with stress life events in predicting changes in adolescent suicidal ideation

Research suggests that genetic variants linked to the hypothalamic-pituitary-adrenal (HPA) axis moderate the association between stressors and change in suicidal ideation, but examining gene-environment interactions with single polymorphisms limits power. This study investigates how interactions between stressful life events and HPA-axis polygenic risk predict changes in suicidal ideation.

A sample of 760 adolescents (M_age = 14.15 ± 0.63 years; 54.6 % girls) was followed up over two years. The polygenic risk was assessed using a multilocus genetic profile score (MGPS) based on the additive effects of six HPA-axis candidate genes (SKS2, NR3C1, NR3C2, FKBP5). Participants were categorized into distinct trajectories of suicidal ideation based on time-varying changes in their ideation scores. Multivariate logistic regression analyses were conducted to identify predictors of trajectory membership.

(1) Five distinct trajectories of suicidal ideation were identified: resistance (52.7 %), persistence (13.1 %), delayed (11.4 %), remission (15.6 %), and relapsing (7.2 %). (2) The combination of HPA-axis MGPS and SLEs showed good predictive accuracy for suicidal ideation trajectories, as indicated by the area under the ROC curve. (3) The interaction between all six stressful life events and HPA-axis MGPS is more predictive of developing persistent trajectories of suicidal ideation. Meanwhile, HPA-axis MGPS interacted with factors such as interpersonal relationships, academic pressure, and loss to better predict the delayed and relapsing suicidal ideation compared to the resistance group.

This study suggests that genetic variants associated with the HPA axis exert a polygenic, additive effect on the relationship between stressful life events and longitudinal increases in suicidal ideation.