Varying Intolerance of Gene Pathways to Mutational Classes Explain Genetic Convergence across Neuropsychiatric Disorders

Abstract

Summary: Genetic susceptibility to intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated in SCZ by genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss-of-function mutations and genes with missense mutations were associated with different pathways across disorders. Conversely, gene expression patterns were specific for each disorder. ID genes were preferentially expressed in the cortex; ASD genes were expressed in the fetal cortex, cerebellum, and striatum; and genes associated with SCZ were expressed in the adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from common pathways that are consistently vulnerable to genetic variations but that spatiotemporal activity of genes contributes to specific phenotypes. : Shahar et al. performed a systematic comparison of genes implicated in intellectual disability, autism spectrum disorder, and schizophrenia. Using systems biology tools, they show that mutation class explains enrichment patterns more than specific disorder. In contrast, they find unique patterns of brain expression for genes associated with each disorder. Keywords: de novo mutations, missense mutations, loss of function mutations, intellectual disability, schizophrenia, autism spectrum disorders, gene expression, constrained genes, systems biology, brain development