Varying intolerance of gene pathways to mutational classes explain genetic convergence across neuropsychiatric disorders

Abstract

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 by SCZ 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 enriched with different pathways, shared with genes intolerant to mutations. Specific gene expression patterns were found for each disorder. ID genes were preferentially expressed in fetal cortex, ASD genes also in fetal cerebellum and striatum, and genes associated with SCZ were most significantly enriched in adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from vulnerable pathways to genetic variations, but spatiotemporal activity of genes contributes to specific phenotypes.