Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S. M., Rippey, C. F., Roccanova, P., Makarov, V., Lakshmi, B., Findling, R. L., Sikich, L., Stromberg, T., Merriman, B., Gogtay, N., Butler, P., Eckstrand, K., Noory, L., Gochman, P., Long, R., Chen, Z., Davis, S., Baker, C., Eichler, E. E., Meltzer, P. S., Nelson, S. F., Singleton, A. B., Lee, M. K., Rapoport, J. L., King, M. C., Sebat, J. (April 2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320 (5875). pp. 539-43.
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adolescent Adult Age of Onset Amino Acid Sequence Brain/cytology/*growth & development/metabolism Case-Control Studies Child Excitatory Amino Acid Transporter 1/chemistry/genetics/physiology Female *Gene Deletion *Gene Duplication Genetic Predisposition to Disease Genome, Human Humans Male Molecular Sequence Data *Mutation Neurons/cytology/physiology Oligonucleotide Array Sequence Analysis Polymorphism, Single Nucleotide Receptor, Epidermal Growth Factor/chemistry/genetics/physiology Schizophrenia/*genetics/physiopathology Signal Transduction |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > mental disorders diseases & disorders > mental disorders > schizophrenia organism description > animal > developmental stage bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function |
| CSHL Authors: | |
| Communities: | CSHL labs > Sebat lab |
| Depositing User: | Matt Covey |
| Date: | 25 April 2008 |
| Date Deposited: | 25 Feb 2013 20:34 |
| Last Modified: | 25 Feb 2013 20:34 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27601 |
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