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

Cell Reports
Shahar ShohatSagiv Shifman

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.

References

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Sep 23, 2011·Nature·Hossein NajmabadiH Hilger Ropers
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Citations

Feb 28, 2018·Molecular Psychiatry·Gabriel E HoffmanKristen J Brennand
Mar 23, 2019·Human Mutation·Paras Garg, Andrew J Sharp
Sep 16, 2020·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Yijia ZhangNa Zhang
Oct 8, 2018·Psychiatry and Clinical Neurosciences·Atsushi Takata
Apr 7, 2019·Molecular Psychiatry·Galya Monderer-RothkoffSagiv Shifman
Apr 30, 2020·International Journal of Molecular Sciences·Francesco RusconiMarco Venturin
Oct 10, 2018·Frontiers in Genetics·Aitana Alonso-GonzalezAngel Carracedo
Oct 14, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Bin LiJinchen Li

Related Concepts

Autism Spectrum Disorders
Profound Mental Retardation
Schizophrenia
Variation (Genetics)
Signal Transduction
Gene Expression
Genetic Predisposition to Disease
Missense Mutation
Genome-Wide Association Study
Brain

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