The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

Social skills group training (SSGT) is one of the most frequently used behavior interventions in children and adolescents with autism spectrum disorder (ASD). Current evidence suggests that the effects are moderate and heterogeneous. Genetic predisposition could be one of the factors contributing to this heterogeneity. Therefore, we used polygenic risk score (PRS) and gene-set analysis to investigate the association between SSGT response and common variants in autistic individuals. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected for genotyping. Polygenic risk scores (PRSs) for ASD, attention deficit hyperactivity disorder (ADHD), and educational attainment (EA) were calculated, and their associations with the intervention outcome at post-intervention and follow-up were tested using mixed linear model. In addition, thirty-two gene sets within five categories (synaptic, glial, FMRP, glutamate, and mitochondrial) were selected to evaluate their role in the intervention outcome. Individuals with higher PRSs for ASD and ADHD had inferior response after SSGT. After multiple test correction, significant results were kept for higher ADHD PRS at follow-up ({beta} = 6.67, p = 0.016). Five gene sets within synaptic category showed modest association with reduced response to SSGT in ASD. Taken together, we provided preliminary evidence that genetic liability calculated using PRS and common variants in synapse gene sets could influence the outcome of SSGT. Our results hold promise for future research into the genetic contribution to individual response to ASD interventions, and should be validated in larger cohorts.