Transcriptional patterns of coexpression across autism risk genes converge on established and novel signatures of neurodevelopment

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N=993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) of 15 neurodevelopmental genes in neuronal cell models. We find that across 70 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. We further show that the degree of convergence is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.14, P = 4.75x10-63) as well as differential expression from transcription studies in post-mortem ASD brains (rho = -0.22, P = 3.62x10-41). After removing genes with minimal evidence of association with ASD, the remaining positively convergent genes are intolerant to mutation, have shorter coding lengths and are enriched for genes with suggestive evidence of contribution to ASD. These results indicate that leveraging convergent coexpression can identify novel ASD risk genes that are more likely to be underpowered and therefore missed by current large-scale sequencing studies. This work ultimately provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known ASD risk genes, and proposes several novel ASD risk gene candidates.