Effects of polygenic liability for autism on neonatal thalamocortical connectivity and behavioral outcomes across sex

Abstract

Functional brain networks are altered in Autism Spectrum Disorder (ASD), with differences in thalamocortical connectivity detectable as early as infancy. ASD shows distinct sex differences, not only in diagnostic rates, but also in brain and behavioral manifestations of the condition. Although common variants account for much of the genetic liability for ASD, little is known about the impact of ASD-associated genetic variation on functional brain connectivity and behavioral outcomes in early life or how this may differ between males and females. Here, we utilize functional MRI (fMRI), genetic, and behavioral data from the Developing Human Connectome Project (dHCP) to investigate sex differences in the association between ASD polygenic scores (PGS), thalamocortical functional connectivity (37-44 weeks postmenstrual age), and behavioral outcomes (18 months) in European term-born infants. We show that across the full sample, higher ASD PGS is associated with weaker thalamic connectivity with posterior parietal cortex, as well as greater ASD-related and ADHD symptoms and slower motor development. Sex differences in the relationship between ASD PGS and thalamic connectivity largely encompassed sensorimotor, posterior parietal, temporal, and insular cortices. Further, in female infants, thalamic connectivity patterns associated with greater genetic liability for ASD were related to poorer motor development. These findings suggest genetic predisposition for ASD shapes early thalamocortical functional connectivity in a sex-specific manner and negatively impacts behavioral development in early toddlerhood.