Executive function mediates the effects of genetic liability to schizophrenia on behavior and functioning in a community sample of children and adolescents

Abstract

Background: Genetic liability for schizophrenia has been associated with cognitive deficits and clinical phenotypes during neurodevelopment. However, the possible role of executive function (EF) as a mediator between the polygenic risk score for schizophrenia (PRS-SZ) and subsequent outcomes, including transdiagnostic general psychopathology (the p-factor), has yet to be examined. In this study, we investigated whether EF mediates the effect of PRS-SZ on psychopathology and functional phenotypes in a community-based youth sample.

Study design: We analyzed cross-sectional data from 698 participants (aged 6-14) of the Brazilian High-Risk Cohort. PRS-SZ was calculated using summary statistics from the Psychiatric Genetics Consortium (PGC-3). EF was assessed through working memory, inhibitory control, and time processing tasks, condensed into a single latent EF trait. Independent linear models were tested to examine direct associations between PRS-SZ and EF, general psychopathology, anxiety symptoms, psychotic experiences (PE), and school performance. Mediation models were applied to evaluate EF as a mediator of the associations between PRS-SZ and each outcome.

Study results: PRS-SZ predicted lower EF scores (β = -0.091, t = -2.435, p = 0.015). No direct associations were found between PRS-SZ and the other measures. EF mediated the association between PRS-SZ and general psychopathology (p-factor) (Effect = 0.0079, BootSE = 0.0049, LLCI = 0.0004, ULCI = 0.0191), anxiety symptoms (Effect = 0.0075, BootSE = 0.0047, LLCI = 0.0001, ULCI = 0.0182), and school performance (Effect = -0.0167, BootSE = 0.0077, LLCI = -0.0327, ULCI = -0.0028), but not PE.

Conclusions: PRS-SZ was associated with poorer EF, which in turn mediated its associations with increased general psychopathology (p-factor) and anxiety symptoms, and reduced school performance in this community youth sample. EF may represent a hub through which PRS-SZ contributes to negative behavioral and functional outcomes.

Keywords: Executive function; Genetics; Neurodevelopment; Psychopathology; Schizophrenia; Youth.