Neural Endophenotypes of Semantic Processing and Social Functioning in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is highly heritable; however, the neural architecture underlying semantic processing and social functioning, and the extent to which it reflects familial liability, remains insufficiently understood. Unaffected siblings (SIB), who share substantial genetic liability with individuals with ASD, offer a critical framework for identifying intermediate neural phenotypes. We examined 36 individuals with ASD, 36 SIB, and 37 typically developing (TD) controls, matched for age, IQ, and handedness. Functional magnetic resonance imaging (fMRI) during a semantic judgment task was used to compare neural activation across groups and to assess whether associations with social functioning, measured by the Social Responsiveness Scale (SRS), reflected familial risk or dimensional continuity across the autism spectrum. Group comparisons revealed a graded endophenotypic pattern in inferior frontal gyrus (IFG) activation, with reduced activation in ASD and intermediate responses in SIB. The middle temporal gyrus (MTG) showed a similar but weaker gradient, with SIB not differing significantly from TD. Both ASD and SIB also demonstrated heightened cuneus activation, consistent with a heritable compensatory shift toward perceptual processing. Importantly, reduced MTG activation, along with a weaker marginal pattern in the IFG, was associated with higher SRS scores in both the familial and full samples, suggesting an association between semantic activation and social functioning. These findings clarify how familial liability and dimensional variation jointly shape the neural organization of semantic processing and social functioning in ASD.