Association between polygenic liability to depression and lifetime depression in at-risk adolescents

Internalising symptoms including depression, anxiety and somatic symptoms in adolescence are common. They can be transient, but they can also persist and progress to major depressive disorder (MDD) Polygenic risk scores for major depression (MD-PGS) may help identify which symptomatic adolescents are at greatest risk of later disorder. In a mega-analysis of two longitudinal population-based cohorts from Brisbane, Australia, we investigated whether polygenic liability to depression improves risk stratification among adolescents with elevated internalising symptoms. Internalising symptoms were assessed at age 14, lifetime MDD was assessed in young adulthood using the Composite International Diagnostic Interview, and MD-PGS were generated using summary statistics from the latest Psychiatric Genomics Consortium major depression genome-wide association study, excluding Australian cohorts. Analyses focused on comparisons between individuals in the top decile of risk and those in the remaining 90% of each cohort. A total of 302 cases with lifetime MDD and 1693 controls were included. Compared with adolescents outside the highest decile of internalising symptoms, those in the top decile at age 14 had a more than two-fold increased odds of lifetime MDD (OR = 2.56, 95% CI 1.92-3.49, p = 5.4 × 10^-10). Individuals in the top decile of MD-PGS also showed increased odds of lifetime MDD compared with the remaining 90% (OR = 3.45, 95% CI 2.53-4.71, p = 4.4 × 10^-¹⁵). Adolescents who were simultaneously in the top decile of both internalising symptoms and MD-PGS had an approximately eight-fold increased odds of lifetime MDD compared with individuals outside the top decile for both risk factors (OR = 8.58, 95% CI 4.04-18.26, p = 1.2 × 10^-⁵). These findings indicate that polygenic risk scores for depression may have particular clinical utility for stratifying risk among adolescents already presenting with elevated internalising symptoms, identifying a subgroup at very high risk for later major depressive disorder.