A regional effort will be undertaken to recruit multiply-affected nuclear families and extended families for study of genetic linkage of schizophrenia-related disorders to loci on a restriction fragment length polymorphism (RFLP) map of the human genome. The use of the gene map makes it possible to analyze linkage to flanking markers in all chromosomal regions, a more powerful form of analysis than when single unmapped markers are studied. Families will be selected that have at least two siblings and one parent with schizophrenia spectrum disorders, and one parent without such a disorder; other available relatives will be studied when they would add significant linkage information. A strategy is described for defining the set of permissible spectrum disorders (including schizotypal and paranoid personality disorders) in each family, with at least one affected individual in each family diagnosed as schizophrenic by RDC and St. Louis criteria. Independent diagnoses will be made from complete case material by a consulting group (Dr. Endicott). Permanent cell lines from members of selected families will be established and stored at the laboratory of Dr. Donis-Keller (Washington University). Each individual's DNA will be genotyped at each of at least 150 polymorphic and relatively evenly-spaced RFLPS. Additional (denser) loci will be studied in regions showing possible linkage in this and other studies. The approach to linkage analysis to be used here (Drs. Green and Lander) can identify one or a small number of single-gene major loci if they are present in a significant proportion of the sample. As loci from all regions will be studied, reports of linkage from other groups can be further assessed as well. Cell lines will be made available to other investigators and repositories on request. Discovery of a gene marker for a form of schizophrenia would represent a major step toward the identification of specific genetic factors in the etiology of this illness.
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