It is widely accepted that genetic transmission is of major etiological importance in the pathogenesis of schizophrenia. Consequently, there has been a major investment in linkage studies using multiplex families segregating schizophrenia, one of the best available methods for elucidating the genetics of complex disease. Unfortunately, schizophrenia, with its non- Mendelian transmission patterns, diagnostic uncertainly, reduced penetrance, phenocopies, and possible genetic heterogeneity, has proven to be a remarkably difficult disease to study with standard linkage techniques. The proposed project aims to search for major genes underlying schizophrenia using four strategies that can address the problems inherent in genetic linkage studies of schizophrenia. 1) With respect to families/subjects, the investigators propose to study exceptionally large multiplex clans in Palau, Micronesia where the population has been geographically and ethnically isolated from outside genetic influences, yet is not inbred. Given the large sibships found in these families, the large number of family members willing to participate, and the greater probability of genetic homogeneity across families in this geographic isolate, the power to detect linkage with these three families is equivalent to the power to detect linkage with 200 small-to medium-sized families. The investigators also plan to ascertain all cases of schizophrenia to be used for future linkage disequilibrium studies in areas of potential linkage found in the current project. 2) With respect to phenotyping, the investigators will phenotype the largest pedigrees using the standard diagnostic phenotype as well as two of the most promising endophenotypes for schizophrenia, SPEM and P50 sensory gating, which offer the advantages of higher penetrances and more clearly defined patterns of inheritance. 3) For genotyping these pedigrees, the investigators will be using a two-pronged approach, including polymorphic candidate genes or regions and a genome scan. 4) The data will be analyzed according to the following specific plans for each study. For Study 1, linkage analysis using the schizophrenia phenotype will be used to test the hypothesis that effects of a major gene contribute to schizophrenia. For Study 2, linkage analysis using psychophysiological endophenotypes will be used. The investigators will use disease status and the two endophenotypes to develop a composite quantitative phenotype which will represent liability for schizophrenia. They will then follow- up all positive results found in Study 1 using this more sensitive phenotype in quantitative linkage analysis.
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