Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

By T. Walsh, J. McClellan, S. McCarthy, A. Addington, S. Pierce, Gregory M. Cooper, A. Nord, M. Kusenda, Dheeraj Malhotra, A. Bhandari and 26 more. Science, 2008

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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.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/b2fa211fb6515802be699bfc3c17b7d0694dddaf

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Citations in the corpus

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “The 109 available data are incomplete but implicate synaptic components, including calcium channel 110 subunits and post-synaptic elements (5, 7-9).”
Similarity network fusion for aggregating data types on a genomic scale (2014, background): “APBA2 is a neuronal adapter, involved in signal transduction processes found to be strongly associated with neuropsychiatric disorders, such as autism [16] and schizophrenia [17].”
Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring (2009, background): “mutations affected genes involved in NMDAR-dependent plasticity of glutamatergic synapses.(84) The genetic findings on schizophrenia and their relation to the dysconnection hypothesis are reviewed in more detail below (fact 3).”
Rare chromosomal deletions and duplications increase risk of schizophrenia (2008, methodology): “Our global burden analysis demonstrated that, on aggregate, single-occurrence and very rare (under about 1 in 1,000) CNVs have increased rates in cases of schizophrenia in comparison with controls, in line with Walsh et al.(2).”
The neurodevelopmental hypothesis of schizophrenia, revisited. (2009, neutral): “The majority of genes identified were disproportionately associated with pathways important for brain development, including synaptic long-term transmission, NRG signaling, axonal guidance, and integrin signaling.(110) A large-scale genome-wide survey of copy number variants (CNVs) performed by the ”
Drosophila strategies to study psychiatric disorders. (2013, background): “Instead, schizophrenia probably results from a ‘common disease-rare allele’ model [116,152,176,180], which proposes that a large diversity of rare genetic variants individually account for the relatively high risk of schizophrenia [117].”
The diagnosis of mental disorders: the problem of reification. (2010, background): “CNV may be inherited (Millar et al. 2000) or may occur de novo in the affected individual, leading to new onset of disorder within a family that can be passed to subsequent generations (T. Walsh et al. 2008).”