Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks

As genes that confer increased risk for autism spectrum disorder (ASD) are identified, a crucial next step is to determine how these risk factors impact brain structure and function and contribute to disorder heterogeneity. With three converging lines of evidence, we show that a common, functional ASD risk variant in the Met Receptor Tyrosine Kinase (MET) gene is a potent modulator of key social brain circuitry in children and adolescents with and without ASD. MET risk genotype predicted atypical fMRI activation and deactivation patterns to social stimuli (i.e., emotional faces), as well as reduced functional and structural connectivity in temporo-parietal regions known to have high MET expression, particularly within the default mode network. Notably, these effects were more pronounced in individuals with ASD. These findings highlight how genetic stratification may reduce heterogeneity and help elucidate the biological basis of complex neuropsychiatric disorders such as ASD. ► The ASD-related risk MET promoter variant alters functional activity and connectivity ► The MET risk allele also disrupts the integrity of major white matter tracts ► Effects are more pronounced in MET-expressing regions and across individuals with ASD ► Findings provide mechanistic insights into gene-brain-behavior relationships in ASD Rudie et al. show how an autism risk factor in the MET gene impacts multiple aspects of brain circuitry in children with and without autism. The study provides new insight into the neurobiological basis of the disorder.