A genetic component to the development of schizophrenia has been established, although the nature of the gene(s) responsible, the mode of inheritance and markers for a genetic locus have not been identified in consistently replicated studies. Over the past 7 years, the present investigators have evaluated, and preserved lymphoblastoid cell lines from greater than 80 USA and 27 UK families with schizophrenic siblings. Laboratory analysis of DNA from these individuals has been proceeding using conventional RFLP probes, and recently polymorphic microsatellite CA repeat markers. Linkage analyses are being performed on all data using established. programs for 2-point lod scores, multipoint and sibling pair analyses. In addition, data is being analyzed using a 2-locus model. The immediate laboratory approach has been based on the hypothesis that a locus for schizophrenia is on the sex chromosomes (suggested by an excess of same over opposite-sex pairs of schizophrenic siblings and an increase of XXY and XXX individuals among schizophrenic subjects). The focus is particularly on the short arm of the X and Y chromosomes, within the pseudoautosomal region and regions more proximal. Positive sib-pair analyses for the distal-most pseudoautosomal locus (DXYS14) and more proximal loci (DXYS17, MIC-2) have been found, with a weak positive 2-point lod score at MIC-2 only. These data are being further analyzed using a 2-locus model; the acquisition of more probe data for other regions of the X chromosome are being accumulated. In addition, CA repeat markers are being used to screen randomly selected regions of the genome spaced throughout the other chromosomes. The proposed renewal of this project is aimed at expanding the clinical collections to a total of 300 nuclear families in order to gain sufficient power for analyses, given the likelihood of etiologic heterogeneity and a complex mode of inheritance. Complete standardized initial clinical and follow-up evaluations will be maintained on all individuals. DNA prepared from the lymphoblastoid cell lines from these families will be used in continual laboratory genomic searches and shared with other investigators whether or not the sex chromosome hypothesis proves to be correct. Linkage analyses will be performed on all accumulated clinical and laboratory data using existing and newly developed programs specifically applicable to complex genetic disorders such as schizophrenia.
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