Rates of rare mutations soar 3 to 4 times higher in schizophrenia

The functional consequences of these structural genetic variations may differ, depending on interactions with other genes or environmental events, say the researchers, making any gene harboring a deleterious structural mutation a “candidate gene.” Any gene harboring one mutation likely contains others. Although each might be individually rare, together such disease-causing variations in one gene could explain a substantial number of illness cases, they suggest.

Among key study findings:

* Genes disrupted in patients, as opposed to healthy participants, were significantly over-represented in pathways critical for brain development. These included genes involved in creating the infrastructure by which neurons communicate -- and for neuronal growth, migration, proliferation, differentiation, and cell death. Among these were genes important for neuronal communications via glutamate and neuregulin, both of which have previously been implicated in schizophrenia.

* The mutations were often specific to single cases or families. Virtually every mutation detected by King, Sebat and colleagues was different in a sample of 150 adults with schizophrenia and 268 healthy controls.

* In families affected by childhood onset schizophrenia, Rapoport and colleagues found that 28 percent (23) of 83 patients harbored mutations, compared with 13 percent (10) of 77 controls. By using the non-transmitted chromosomes of the patients’ parents as controls, the researchers were able to determine if the mutations in their children were likely inherited or spontaneous. The majority turned out to be inherited rather than spontaneous, some from parents unaffected by the illness. Childhood onset schizophrenia is thought to be a more severe and more genetically influenced form of the illness.

The research was also funded by the Forrest C. and Frances H. Lattner Foundation, NARSAD, the Simons Foundation, the Stanley Medical Research Foundation, the Howard Hughes Medical Institute.

Rare Structural Variants Distrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Tom Walsh1*, Jon M. McClellan2*#, Shane E. McCarthy3*, Anjene M. Addington4*, Sarah B. Pierce1, Greg M. Cooper5, Alex S. Nord5, Mary Kusenda3, Dheeraj Malhotra3, Abishek Bhandari3, Sunday M. Stray1, Caitlin F. Rippey5, Patricia Roccanova3, Vlad Makarov3, B. Lakshmi3, Robert L. Findling6, Linmarie Sikich7, Thomas Stromberg4, Barry Merriman8, Nitin Gogtay4, Philip Butler4, Kristen Eckstrand4, Laila Noory4, Peter Gochman4, Robert Long4, Amalia Dutra9, Zugen Chen8, Sean Davis10, Carl Baker5, Evan E. Eichler5, Paul S. Meltzer10, Stanley Nelson8, Andrew B. Singleton11, Ming K. Lee1, Judith L. Rapoport4, Mary-Claire King1, 5, Jonathan Sebat3.