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

•ASD genes from multiple sources converge on prenatal neurodevelopmental processes•Transcriptional and translational coregulation link ASD genes at multiple levels•Multiple ASD risk gene modules are enriched in superficial cortical layers•These patterns highlight features that distinguish ASD from intellectual disability

SummaryGenetic 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (334 K)Download as PowerPoint slide