Understanding how depression genetic liability shapes executive function: Epidemiological evidence for symptom-mediated pathways

J Affect Disord. 2026 May 29:122059. doi: 10.1016/j.jad.2026.122059. Online ahead of print.

ABSTRACT

Executive function (EF) impairments are common in depression (MD), yet the developmental pathways linking MD genetic liability to cognitive outcomes remain unclear. In this study, we examined whether genetic liability to MD is associated with EF performance at ages 11 and 15 in a Brazilian population-based birth cohort and assessed whether MD symptoms in adolescents and their mothers mediate these associations. Data were drawn from the 2004 Pelotas Birth Cohort (Brazil), including 3206 participants at age 11 and 1753 at age 15. EF was assessed using selective attention and cognitive flexibility tasks at age 11 and spatial working memory at age 15. A polygenic score for MD (MD-PGS), derived from a trans-ancestry genome-wide association study (GWAS) using SBayesRC, was examined in relation to EF using structural equation modeling, considering adolescent and maternal MD symptoms as potential mediators. Higher MD-PGS were associated with EF performance in adolescence. In adjusted models, a one-SD increase in MD-PGS was associated with worse selective attention at age 11 (β = 0.15, p = 0.012) and poorer working memory at age 15 (β = 0.52, p = 0.011). Mediation analyses showed that adolescent MD symptoms partially mediated the associations between MD-PGS and EF, ranging from 7% to 12%. After adjustment for socioeconomic factors, indirect effects through maternal MD symptoms were attenuated across all EF domains. These findings underscore the role of familial emotional environments in shaping cognitive development. Identifying these mediating pathways is crucial for early prevention efforts, as reducing MD symptoms may lessen downstream impacts on cognitive development.

PMID:42217641 | DOI:10.1016/j.jad.2026.122059