This project addresses two major bottlenecks to progress in detecting susceptibility genes for schizophrenia: 1) the probable genetic heterogeneity of the schizophrenia disorders and 2) uncertainty over the boundaries of the schizophrenia phenotype. This project was stimulated by the hypothesis that early (childhood) onset schizophrenia is associated with increased genetic loading for this disorder. The proposed project will replicate and extend important findings from the first phase of this project indicating that there is a significantly increased familial aggregation of schizophrenia, schizophrenia spectrum personality disorders, and certain neurocognitive impairments in families of probands with childhood-onset schizophrenia compared to families of community control and adult-onset schizophrenia probands. The long-term stability and predictive validity of schizophrenia spectrum diagnoses and neurocognitive impairments detected during adolescence in the siblings of probands with childhood-onset schizophrenia will be determined. Hypotheses about the role obstetric complications play in triggering an early onset of schizophrenia and about the relation between history of obstetric complications and impaired functioning of the hippocampal/temporal lobes will be tested. The hypothesis that relatives of probands with childhood-onset schizophrenia who have neurocognitive impairments will show subtle signs of formal thought disorder impaired discourse and impairments in working memory will also be tested. The proposed project will test a number of genetic models of the familial transmission of putative measures of the extended schizophrenia phenotype, including analyses to examine the evidence for a single vulnerability factor versus two familial vulnerability factors (one influencing mainly neurocognitive measures and the other mainly schizophrenia spectrum diagnosis. Whether chromosomal regions found in prior research to be associated with susceptibility to schizophrenia are associated with susceptibility to childhood-onset schizophrenia and potentially associated phenotypes (including neurocognitive impairments) will be determined.
These specific aims will be addressed by rediagnosing all previously studied (N = 50) probands and relatives with childhood-onset schizophrenia to confirm their original diagnoses, enrolling an additional 90 new families of probands with childhood-onset schizophrenia and 60 families of probands of community controls, and capitalizing on data from 120 families of adult-onset schizophrenia probands which has already been collected. We will conduct a genetic linkage analysis to determine whether putative susceptibility genes identified in prior research are associated with the presence of schizophrenia spectrum disorders and/or neurocognitive impairments in families of probands with childhood-onset schizophrenia. DNA will be retained for use in future linkage, linkage disequilibrium, association and other studies.
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