EBD Blog

A multi-institution research team has discovered that rare mutations, which probably affect development in the human nervous system, may significantly increase the risk of schizophrenia. The researchers found that adults with schizophrenia or schizoaffective disorder and youth with childhood onset schizophrenia (COS) were 3 to 4 times more likely to have rare structural variants that deleted or duplicated one or a few genes. They say that the disrupted genes are “over-represented in pathways important for brain development.

Under the heading “Rare Mutations Hint at Multiple Schizophrenias,” Constance Holden of ScienceNOW Daily News described the finding in this way:

Suspecting that rarer mutations might play a stronger role in schizophrenia, two teams of researchers looked for uncommon deletions or duplications of tiny DNA sequences within genes that occur only in individual patients or their close relatives. One team, led by medical geneticist Thomas Walsh at the University of Washington, Seattle, found these rare so-called copy number variants in 15% of 150 schizophrenics they surveyed. Only 5% of 268 healthy controls carried the same variants. The other team, at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, examined DNA from 83 people with severe forms of the disease diagnosed before the age of 13 and compared them with 77 controls. Among this early-onset group, 20% had rare copy number variants–four times the rate in the controls.

The research is to be published in Science next week. The abstract is available on line but subscribers to the journal (including members of the American Association for the Advancement of Science) can read the full article on line now.

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

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

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 kb were identified by microarray comparative genomic hybridization (CGH) 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 (P = 0.0008) and 20% of young onset cases (P = 0.0001). The association was independently replicated in patients with childhood-onset schizophrenia compared to their parents (P = 0.03). Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations impacting genes in neurodevelopmental pathways contribute to schizophrenia.

Links:

• The full article;
• The abstract shown here
• Ms. Holden’s story.