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

Shahar Shohat, Eyal Ben-David, Sagiv Shifman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageAmerican English
Pages (from-to)2217-2227
Number of pages11
JournalCell Reports
Volume18
Issue number9
DOIs
StatePublished - 28 Feb 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

Keywords

  • autism spectrum disorders
  • brain development
  • constrained genes
  • de novo mutations
  • gene expression
  • intellectual disability
  • loss of function mutations
  • missense mutations
  • schizophrenia
  • systems biology

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