This is an application for competitive continuation of our research on the genetic etiology of schizophrenia in Palau, a geographic and ethnic isolate in Micronesia that is not inbred. The completion of the epidemiological phase of our Palau study has laid the foundation for the proposed prospective study of high-risk (HR) offspring in the large multiplex schizophrenia families that have now been identified. We plan to study not only all 14-18 year-old adolescent offspring of affected parents (approximately 100) but also the adolescent offspring of unaffected parents who are possible carriers of a genetic liability for psychotic illness (approximately 200). These 300 HR adolescents will be compared to 100 14-18 year olds who are identified as behaviorally but not genetically at risk (adolescents with no close affected relatives who have been referred for substance abuse counseling, psychosocial counseling, or psychiatric treatment) and 100 normal adolescent controls. All subjects will be comprehensively assessed with a battery of clinical/psychosocial and neuropsychological measures plus two neurophysiological endophenotypes for schizophrenia and followed up longitudinally for the development of psychopathology in order to accomplish three specific aims. 1. Describe the genetic epidemiology of schizophrenia in HR offspring within multiplex families. 2. Develop and test etiological models that describe how genetic liability, environmental factors, and individual traits interact to cause schizophrenia spectrum psychopathology. 3. Describe the phenomenology of schizophrenia in its developmental stages to facilitate early detection and intervention. Our proposed study has a number of unique characteristics that will greatly enhance the information it generates. Compared to prior studies of HR offspring, we will be able to sample a broader range of relationships to schizophrenic patients and a broader range of parental clinical phenotypes that can transmit schizophrenia spectrum psychopathology. Also, a unique component of our study design is the comparison of genetically HR subjects with a group of behaviorally, but not genetically, HR subjects, which may help to disentangle environmental precursors of schizophrenia from genetic liability. Furthermore, our study proposes to fill existing gaps in the assessment of MR offspring by adding several measures including two promising endophenotypes for schizophrenia, saccadic ocular motor dysfunction and P50 sensory gating deficits.
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