W90. MAJOR DEPRESSIVE DISORDER AMPLIFIES THE COMBINED EFFECT OF POLYGENIC RISK AND CHILDHOOD TRAUMA ON RISK OF LIFETIME SUICIDE ATTEMPT

Suicidal behavior emerges from a complex interplay of genetic and environmental risk factors. Prior findings show that cumulative childhood trauma (CT) moderates the effect of suicide attempt (SA) polygenic risk score (SA PRS), with genetic risk more strongly associated with SA among individuals exposed to greater trauma. However, it is unclear whether this relationship varies by history of major depressive disorder (MDD), another key risk factor for suicidal behavior. MDD may reflect or exacerbate the expression of genetically influenced traits and may intensify the influence of genetic risk for suicide, particularly when combined with early-life trauma. This study examined whether lifetime MDD status moderates the interaction between SA PRS and CT in predicting lifetime SA using a PRS derived from the largest GWAS meta-analysis of SA to date (N = 958,896; present analyses restricted to European (EUR) ancestry participants [35,311 cases/777,575 controls]). Data were analyzed from 3,176 EUR adults who participated in the Yale-Penn study, which was designed for genetic research on psychiatric and substance use disorders. PRS-CS software was used to generate the PRS. Logistic regression tested associations between PRS and lifetime suicide attempt, adjusting for age, sex, the top 10 genetic principal components, lifetime MDD, and CT. Two- and three-way interactions between SA PRS, CT, and MDD were also included. Twelve percent of the sample (N=379) reported a suicide attempt, and 16.7% (N=519) reported MDD. Higher SA PRS (OR=1.46, 95%CI=1.29-1.65), cumulative CT (OR=1.82, 95%CI=1.62-2.03), and MDD diagnosis (OR=2.39, 95%CI=1.82-3.13) were each independently associated with suicide attempt. A three-way interaction also emerged (SA PRS × cumulative CT × MDD; OR=1.48, 95%CI=1.14–1.89), suggesting MDD modifies the joint effect of genetic risk and childhood trauma on suicide attempt. Among individuals with MDD (Figure 1), the predicted probability of suicide attempt increased from 12% (low PRS, no trauma) to 61% (high PRS, high trauma), compared to a smaller increase—from 2% to 32%—in those without MDD (Figure 2). MDD shapes how polygenic risk and early-life adversity interact to influence suicide risk. The combined effect of genetic liability and childhood trauma was substantially greater among individuals with MDD than those without, indicating MDD may amplify the impact of this gene-environment interaction. MDD may reflect underlying vulnerabilities—such as heightened stress reactivity—that increase susceptibility to suicide attempts. Incorporating polygenic risk information alongside diagnostic and trauma history may enhance risk stratification and support more precise prevention efforts.