Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia.

Genetic factors play an important part in the development of schizophrenia and bipolar disorder, and linkage analyses in families have successfully identified several chromosomal regions containing candidate genes. A single large pedigree has been described in which schizophrenia and depression segregate with a balanced chromosomal translocation involving the long arm of chromosome 1 and the short arm of chromosome 11. The gene named DISC1, disrupted at the chromosome 1 breakpoint, is a novel candidate gene that may have a role in the pathogenesis of schizophrenia. The cellular location and function of the protein coded by DISC1 is currently being investigated. The phenotype associated with DISC1 in the t (1;11) translocation family includes schizophrenia, schizoaffective disorder, recurrent major depression and bipolar disorder. Hence this locus is one of several now reported apparently showing linkage to both schizophrenia and bipolar disorder. The study of intermediate phenotypes or "endophenotypes" may clarify the relations between phenotype and genotype. Auditory event related potentials are EEG based physiological measures widely studied in schizophrenia. In particular the cognitive evoked potential, the P300 response generated during an "odd-ball" two-tone discrimination task consistently shows reduced amplitude in schizophrenia compared to controls. In members of the family with the t (1;11) translocation, P300 amplitude was reduced in relatives who carried the translocation compared to relatives with a normal karyotype. Furthermore the amplitude reduction was independent of the presence or absence of symptoms because asymptomatic translocation carriers showed similar P300 amplitude reduction as was found in translocation carriers who were diagnosed with schizophrenia, bipolar disorder or unipolar depression. The results confirm that subjects with schizophrenia who carry the t (1;11) translocation have similar phenotype to unrelated subjects with schizophrenia and a normal karyotype. Furthermore P300 amplitude may be a useful intermediate phenotype detecting the neuropathology of schizophrenia in "at risk" individuals even in the absence of clinical symptoms.