Unveiling the role of IGF1R in autism spectrum disorder: a multi-omics approach to decipher common pathogenic mechanisms in the IGF signaling pathway

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by impairments in social interaction, communication, and repetitive behaviors. Emerging evidence suggests that the insulin-like growth factor (IGF) signaling pathway plays a critical role in ASD pathogenesis; however, the precise pathogenic mechanisms remain elusive. This study utilizes multi-omics approaches to investigate the pathogenic mechanisms of ASD susceptibility genes within the IGF pathway. Whole-exome sequencing (WES) revealed a significant enrichment of rare variants in key IGF signaling components, particularly the IGF receptor 1 (IGF1R), in a cohort of Chinese Han individuals diagnosed with ASD, as well as in ASD patients from the SFARI SPARK WES database. Subsequent single-cell RNA sequencing (scRNA-seq) of cortical tissues from children with ASD demonstrated elevated expression of IGF receptors in parvalbumin (PV) interneurons, suggesting a substantial impact on their development. Notably, IGF1R appears to mediate the effects of IGF2R on these neurons. Additionally, transcriptomic analysis of brain organoids derived from ASD patients indicated a significant association between IGF1R and ASD. Protein-protein interaction (PPI) and gene regulatory network (GRN) analyses further identified ASD susceptibility genes that interact with and regulate IGF1R expression. In conclusion, IGF1R emerges as a central node within the IGF signaling pathway, representing a potential common pathogenic mechanism and therapeutic target for ASD. These findings highlight the need for further investigation into the modulation of this pathway as a strategy for ASD intervention.