Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach

Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) risk genes in ASD, which individually do not meet the ASD liability threshold but contribute to risk when paired with another MES risk gene. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES risk genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered jointly, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs' contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD's genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder's etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD's genetic underpinnings and developing targeted therapeutic strategies.