23. UNDERSTANDING HOW DEPRESSION GENETIC LIABILITY SHAPES EXECUTIVE FUNCTION: EPIDEMIOLOGICAL EVIDENCE FOR SYMPTOM-MEDIATED PATHWAYS IN THE 2004 PELOTAS (BRAZIL) BIRTH COHORT

Background Executive functions (EF) are fundamental to cognitive and emotional development,yet are frequently impaired in depression. The mechanisms underlying this association remain unclear, particularly the roles of genetic liability and symptom-related pathways. One proposed mechanism is pleiotropy, whereby genetic factors increasing susceptibility to depression also influence EF through shared biological processes. Additionally, genetic liability may extend beyond the individual, shaping adolescents’ mental health and family environments. Emerging evidence suggests that adolescents’ genetic risk can influence parental behavior and mental health through evocative gene–environment correlation processes. In this context, maternal depressive symptoms may represent an important pathway linking genetic risk to EF outcomes. This study examined whether genetic predisposition to major depression, indexed by a polygenic score (MD-PGS), is associated with EF in adolescence, and whether adolescent and maternal depressive symptoms mediate these associations. Methods This study draws data from adolescents enrolled in the 2004 Pelotas (Brazil) Birth Cohort, a population-based longitudinal study. EF was assessed at ages 11 (selective attention and cognitive flexibility) using the Test of Everyday Attention for Children, and at age 15 (working memory) using the Cambridge Neuropsychological Test Automated Battery. Genetic data were obtained from DNA collected at age 6 and genotyped using the Global Screening Array, Illumina v2. Participants with both genetic data and EF measures were included in the analytic sample, yielding 3,206 individuals at age 11 and 1,753 at age 15. MD-PGS was derived from a large trans-ancestry GWAS. Associations between MD-PGS and EF were examined using linear regression models adjusted for sex and ancestry principal components. Mediation analyses were conducted using structural equation modeling to assess indirect effects via adolescent and maternal depressive symptoms measured at corresponding ages. Results Higher MD-PGS was associated with poorer EF performance. After adjustment, significant associations remained for selective attention at age 11 and working memory at age 15, but not for cognitive flexibility. A one–SD increase in MD-PGS was associated with a 0.18-point increase in selective attention scores (β = 0.18, 95% CI: 0.06;0.29, p = 0.003) and a 0.63-point increase in working memory performance (β = 0.63, 95% CI: 0.24;1.03, p = 0.002). The variance explained by MD-PGS (ΔR²) ranged from 0.26% for selective attention to 0.52% for working memory. Mediation analyses indicated that adolescent depressive symptoms partially explained these associations, accounting for 6–10% of the total effect. Similarly, maternal depressive symptoms mediated 8–13% of the associations, suggesting indirect pathways through the family environment. Discussion These findings support a model in which genetic liability to depression influences EF both directly and indirectly via depressive symptoms. The results highlight the importance of considering individual and intergenerational pathways linking genetic risk to cognitive development. Interventions targeting depressive symptoms in adolescents and mothers may mitigate adverse effects on EF. This study contributes to limited literature on psychiatric genomics in low- and middle-income settings and underscores the relevance of integrating genetic and environmental mechanisms in developmental research.