title: 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 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.
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Shahar
authors.initials: S
authors.lastname: Shohat
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Ben-David
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address: sagiv.shifman@mail.huji.ac.il.
authors.forename: Sagiv
authors.initials: S
authors.lastname: Shifman
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
keywords: autism spectrum disorders; brain development; constrained genes; de novo mutations; gene expression; intellectual disability; loss of function mutations; missense mutations; schizophrenia; systems biology