Schizophrenia and affective disorders - Cosegregation with a translocationat chromosome 1q42 that directly disrupts brain-expressed genes: Clinical and P300 findings in a family

A family with a (1;11)(q42;q14.3) translocation significantly linked to a c linical phenotype that includes schizophrenia and affective disorders is de scribed. This translocation generates a LOD score of 3.6 when the disease p henotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all clas sed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features b y which the psychiatric phenotype could be distinguished from unrelated cas es of either schizophrenia or affective disorders, and no physical, neurolo gical, or dysmorphic conditions co-occurred with psychiatric symptoms. Tran slocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and dif ferent from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carrier s of the translocation who had no psychiatric symptoms-a pattern found in o ther families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of k aryotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a dis ease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.