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Schizophrenia Bulletin Advance Access published online on May 12, 2006
Schizophrenia Bulletin, doi:10.1093/schbul/sbj079
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© The Author 2006. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Article

Beyond Schizophrenia: The Role of DISC1 in Major Mental Illness

William Hennah 1 *, Pippa Thomson 2, Leena Peltonen 3, and David Porteous 2
1 Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
2 Medical Genetics Section, University of Edinburgh, Edinburgh, Scotland
3 Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; The Broad Institute, Massachusetts Institute of Technology, Boston, MA, USA

* To whom correspondence should be addressed.
William Hennah, E-mail: william.hennah{at}ktl.fi


  Abstract

Schizophrenia and related disorders have a major genetic component, but despite much effort and many claims, few genes have been consistently replicated and fewer have biological support. One recent exception is "Disrupted in Schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses. Since then, genetic analysis has implicated DISC1 in schizophrenia, schizoaffective disorder, bipolar affective disorder, and major depression. Importantly, evidence is emerging from genetic studies for a causal relationship between DISC1 and directly measurable trait variables such as working memory, cognitive aging, and decreased gray matter volume in the prefrontal cortex, abnormalities in hippocampal structure and function, and reduction in the amplitude of the P300 event-related potential. Further, DISC1 binds a number of proteins known to be involved in essential processes of neuronal function, including neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction. Thus, both genetic and functional data provide evidence for a critical role for DISC1 in schizophrenia and related disorders, supporting the neurodevelopmental hypothesis for the molecular pathogenesis of these devastating illnesses.

Keywords: genetics; animal models; neuroimaging; expression studies; neurodevelopment.
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