Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia by Walsh Tom, McClellan Jon M, McCarthy Shane E, Addington Anjené M, Pierce Sarah B, Cooper Greg M, Nord Alex S, Kusenda Mary, Malhotra Dheeraj, Bhandari Abhishek, Stray Sunday M, Rippey Caitlin F, Roccanova Patricia, Makarov Vlad, Lakshmi B, Findling Robert L, Sikich Linmarie, Stromberg Thomas, Merriman Barry, Gogtay Nitin, Butler Philip, Eckstrand Kristen, Noory Laila, Gochman Peter, Long Robert, Chen Zugen, Davis Sean, Baker Carl, Eichler Evan E, Meltzer Paul S, Nelson Stanley F, Singleton Andrew B, Lee Ming K, Rapoport Judith L, King Mary-Claire, Sebat Jonathan in Science (New York, N.Y.) (2008).

[PMID: 18369103] PubMed


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.

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