Integrative Functional Genomic Analyses Implicate Specific Molecular Pathways and Circuits in Autism

Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: (1) do these genetic loci converge on specific biological processes, and (2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto coexpression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest that translational regulation by FMRP and transcriptional coregulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD. [Display omitted] •Exome sequencing identifies an ASD gene, Ankyrin 2, neuronal (ANK2)•Data from developing human brain are used for coexpression analyses of nine ASD genes•ASD genes converge in midfetal frontal cortex deep projection neurons•Approach clarifies when, where, and in what cell type to study specific ASD mutations Network analysis of nine genes previously implicated in autism spectrum disorders (ASD) identifies a key point of convergence in midfetal deep frontal cortex glutamatergic projection neurons, providing a temporal and spatial framework for studying ASD pathophysiology.