Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

TLDR

Schizophrenia is a devastating neurodevelopmental disorder whose genetic underpinnings remain largely unknown. The study tests whether individually rare structural variants contribute to schizophrenia risk. Researchers identified and validated microdeletions and microduplications larger than 100 kb in 150 schizophrenia patients and 268 ancestry‑matched controls using microarray comparative genomic hybridization and high‑resolution platforms. Rare structural variants were found in 15 % of cases (20 % of young‑onset) versus 5 % of controls, replicated in childhood‑onset patients versus parents, and disproportionately disrupted neurodevelopmental signaling genes such as neuregulin and glutamate pathways, supporting a role for multiple rare mutations in schizophrenia.

Abstract

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.