Journal Article

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

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

2008

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Adolescent / Adult / Adult and adolescent clinical studies / Age of Onset / Amino Acid Sequence / Amino acids / Autistic disorder / Biological and medical sciences / Brain - cytology / Brain - growth & development / Brain - metabolism / Case-Control Studies / Child / Chromosomes / Classical genetics, quantitative genetics, hybrids / comparative genomic hybridization / Diseases / DNA / Excitatory Amino Acid Transporter 1 - chemistry / Excitatory Amino Acid Transporter 1 - genetics / Excitatory Amino Acid Transporter 1 - physiology / Female / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene Duplication / Genes / Genetic mutation / Genetic Predisposition to Disease / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genome, Human / Genomics / glutamic acid / Human / Humans / Male / Medical genetics / Medical sciences / Mental disorders / microarray technology / Molecular Sequence Data / Mutation / neurodevelopment / Neurons - cytology / Neurons - physiology / Oligonucleotide Array Sequence Analysis / parents / patients / Polymorphism, Single Nucleotide / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Psychoses / Receptor, Epidermal Growth Factor - chemistry / Receptor, Epidermal Growth Factor - genetics / Receptor, Epidermal Growth Factor - physiology / Receptor, ErbB-4 / Schizophrenia / Schizophrenia - genetics / Schizophrenia - physiopathology / Signal Transduction