Contributions of PTSD polygenic risk and environmental stress to suicidality in preadolescents

Suicidal ideation and attempts (i.e., suicidality) are complex behaviors driven by environmental stress, genetic susceptibility, and their interaction. Preadolescent suicidality is a major health problem with rising rates, yet its underlying biology is understudied. Here we studied effects of genetic stress susceptibility, approximated by the polygenic risk score (PRS) for post-traumatic-stress-disorder (PTSD), on preadolescent suicidality in participants from the Adolescent Brain Cognitive Development (ABCD) Study®. We further evaluated PTSD-PRS effects on suicidality in the presence of environmental stressors that are established suicide risk factors. Analyses included both European and African ancestry participants using PRS calculated based on summary statistics from ancestry-specific genome-wide association studies. In European ancestry participants (N = 4,619, n = 378 suicidal), PTSD-PRS was associated with preadolescent suicidality (odds ratio [OR] = 1.12, 95%CI 1-1.25, p = 0.038). Results in African ancestry participants (N = 1,334, n = 130 suicidal) showed a similar direction but were not statistically significant (OR = 1.21, 95%CI 0.93-1.57, p = 0.153). Sensitivity analyses using non-psychiatric polygenic score for height and using cross-ancestry PTSD-PRS did not reveal any association with suicidality, supporting the specificity of the association of ancestry-specific PTSD-PRS with suicidality. Environmental stressors were robustly associated with suicidality across ancestries with moderate effect size for negative life events and family conflict (OR 1.27-1.6); and with large effect size (OR ∼ 4) for sexual-orientation discrimination. When combined with environmental factors, PTSD-PRS showed marginal additive effects in explaining variability in suicidality, with no evidence for G × E interaction. Results support use of cross-phenotype PRS, specifically stress-susceptibility, as a genetic marker for suicidality risk early in the lifespan.