Parental educational attainment polygenic scores contribute to phenotypic heterogeneity in offspring with autism

Educational attainment-related polygenic scores have been implicated in autism spectrum disorder (ASD), but how parental polygenic scores shape offspring phenotypes remains unclear. Using genotyping and exome-sequencing data from 142,357 individuals (55,252 ASD cases) in a large ASD cohort, we dissected the direct and indirect genetic effects of educational attainment-related polygenic scores on ASD phenotypes. Trio-model analyses showed that parental polygenic scores for educational attainment (PGS _EA ) were associated with milder core ASD symptoms, including social deficits and repetitive behaviors, predominantly through indirect genetic effects, whereas their associations with comorbidities were driven predominantly by direct genetic effects. PGS _EA was also significantly negatively associated with rare variant burden and prenatal factors, although these factors contributed largely independently to most phenotypes. Adjustment for full-scale intelligence quotient (FSIQ) and socioeconomic status (SES) partially attenuated the indirect effects of PGS _EA on offspring phenotypes. Finally, higher parental PGS _EA was associated with later age at diagnosis in offspring, partly through its protective effects on ASD phenotypes. These findings indicate that indirect genetic effects of parental PGS _EA contribute substantially to phenotypic variation in ASD and highlight family-mediated pathways as an important component of ASD heterogeneity.