Advancing a functional genomics for schizophrenia: psychopathological and cognitive phenotypes in mutants with gene disruption

Schizophrenia is a complex, heritable psychotic disorder in which numerous genes and environmental adversities appear to interact in determining disease phenotype. In addition to genes regulating putative pathophysiological mechanisms, a new generation of molecular studies has indicated numerous candidate genes to be associated with risk for schizophrenia. The present review focuses on studies in mice mutant for genes associated with putative pathophysiological mechanisms and candidate risk genes for the disorder. It seeks to evaluate the extent to which each mutation of a schizophrenia-related gene accurately models multiple aspects of the schizophrenia phenotype or more circumscribed, distinct endophenotypes in terms of psychopathology and pathobiology; in doing so, it places particular emphasis on positive symptoms, negative symptoms and cognitive dysfunction. To further this goal, it juxtaposes continually evolving mutant genomics with emergent clinical genomic studies. Opportunities and challenges associated with the use of such mutants, including diagnostic specificity and the translational barrier associated with modelling schizophrenia, are discussed. The potential value of genetic models for exploring gene-gene and gene-environment interactions relating to schizophrenia is highlighted. Elucidation of the contribution of genetic variation to specific symptom clusters and underlying aspects of pathobiology will have important implications for identifying treatments that target distinct domains of psychopathology and dysfunction on an individual patient basis.