Genetic factors constitute the most important known risk factor for schizophrenia. We request in this application three years of continued support for a multi-faceted epidemiologic project, the goal of which is to increase our knowledge of the role of genetic factors in the etiology of schizophrenia. The project has two components: i) a case controlled family study of schizophrenia based on the psychiatric and electoral registries of County Roscommon, Ireland, and ii) a high density study of families with multiple cases of schizophrenia ascertained systematically from the entire island of Ireland (the Republic of Ireland and Northern Ireland). This renewal has three major goals. The first is to complete the ascertainment, study and sampling of families with a high density of schizophrenia from throughout the island of Ireland. Evidence is presented that the sample size required for high power to detect linkage for a disorder like schizophrenia is much larger than that needed for classic mendelian traits. Ireland represents an ideal environment in which to conduct such studies, as is proven by our work accomplished to date. Our second goal is to use the extensive clinical data obtained on affected members of these high-density pedigrees to search for patterns of clinical heterogeneity within schizophrenia that are transmitted within families. Such patterns, if detected, can serve as the basis of a priori tests for heterogeneity in future linkage analyses. Our third goal is to conduct further data analysis of our recently completed case-controlled family study to address such issues as the boundaries of the schizophrenia spectrum, the relationship between major clinical features of schizophrenia such as age at onset and outcome and the familial vulnerability to illness and the association between personality traits such as introversion, social anhedonia and magical thinking and the familial liability to schizophrenia.
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