Evidence from family, twin and adoption studies indicates that genetic factors are involved in the etiology of schizophrenia and related conditions, yet the mode of inheritance of schizophrenia and the locus of the predisposing gene or gene is unknown. Although recent advances in molecular and quantitative genetics have contributed to the localization of the genes responsible for a number of neuropsychiatric diseases, application of these new technologies to schizophrenia has been difficult because of severe problems in methodology: The phenotypic boundaries of schizophrenia are unclear, a large number of families are needed to test genetic models, many linkage probes are needed to screen the genome, and robust quantitative analysis techniques are needed to analyze the data. Investigators have attempted to overcome some of these difficulties by the use of large, multigeneration pedigrees with a large number of affected members. The results of this approach have been equivocal and the relationship between the commonly observed forms of disease and the atypical forms seen in high density families is unknown. We propose to do linkage and segregation analysis on the form(s) of schizophrenia seen in typical schizophrenic families. Most importantly, we will be able to test the genetic relationship between chronic schizophrenia and the less severe forms of disease -- referred to as """"""""spectrum disorders"""""""" -- often seen in families of schizophrenic patients. We will also test the genetic relationship between schizophrenia and smooth pursuit eye movement disorders (SPEM) that have been reported as associated with schizophrenia and the spectrum disorders. Families identified by the Family Studies Core will be identified through a schizophrenic proband and the probands will be ascertained in a systematic way that will allow us to do a segregation analysis. The Family Studies Core will do extensive diagnostic evaluations on each family member to identify those family members with schizotypal personality. Data on other neuropsychiatric measures such as SPEM and CT scans will also be collected. Blood samples will be drawn from all family members and the lymphocytes immortalized. We will do RFLP markers on all families, starting with chromosome 5 and several candidate genes, such as the D2 receptor, and then using the most polymorphic DNA probes available for other parts of the genome. We will be able to test the hypotheses that the spectrum disorders are genetically related to chronic schizophrenia as well as whether SPEM abnormalities are a subclinical marker for at least part of the schizophrenia genotype. Segregation analysis will allow us to test whether any of the appropriately defined phenotypes follow a mendelian pattern of inheritance. These definitions will also be used in the linkage analysis. Previous work has shown that by correctly identifying a subclinical marker, such as SPEM or the spectrum disorders, a linkage an be detected where none was detectable if only the frame disease is included in the affected phenotype. Our definitions of possible phenotypes will be predefined and conservative. While heterogeneity within schizophrenia remains a possible confounding problem, our sample size is sufficient to be able to detect a major form of the disease even if only about 40% to 60% of the families are represent a homogeneous form linked to one marker.
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