Autism Mutations Preferentially Target Distributed Brain Circuits and Cell Types Associated with Sensory Integration and Decision Making

Autism spectrum disorder (ASD) is a highly heritable psychiatric condition characterized by difficulties in social communication and stereotypic, repetitive behaviors. Genetics studies have discovered many dozens of genes with causal roles in autism, and functional analyses have demonstrated that ASD-associated mutations affect a diverse range of brain regions and cell types. However, the precise mechanisms by which these genetic alterations lead to autism-related phenotypes remain unclear. Psychiatric cognitive and behavioral traits are believed to arise from dysfunction of specific brain circuits formed by anatomically and functionally connected brain areas. To identify the circuits and cell types primarily affected by ASD mutations, we developed an unbiased approach, GENCIC, which computationally integrates genome-wide genetic data with a brain-wide spatial mouse transcriptome and an anatomical mesoscale connectome. Applying this approach to ASD reveals a convergence of mutations on cohesive brain circuits that are enriched in long-distance connections and span both cortical and subcortical brain structures. Furthermore, our analysis of brain-wide single-cell spatial transcriptomics shows that the heterogeneity of circuit structures affected in ASD is matched by the substantial diversity of strongly impacted circuit cell types. Notably, the implicated circuits and cell types play a central role in the integration of multimodal sensory and emotional information and in decision-making based on this information. We also find that different circuit structures exhibit distinct vulnerability patterns that correlate with cognitive phenotypes in ASD. Overall, our study demonstrates how ASD-related genetic mutations impact multiple levels of brain organization, ultimately disrupting functional circuits that drive core autism-related behaviors.