Schizophrenia is a serious neuropsychiatric illness estimated to affect 1.3 percent of the adult population in the United States. Family, twin and adoption studies have demonstrated that schizophrenia is predominantly genetic, with a high heritability. The complex genetics, phenotypic uncertainty, and unclear role of environmental interactions have led to the discouraged view that significant genetic linkage will not be easily obtained. None of the linkage reports published to date detail a finding of significant magnitude to serve as a starting point for positional cloning. We have recently concluded a genome-wide search for loci contributing to risk for schizophrenia, and multipoint analysis with markers from 1q21-22 have produced a maximum LOD score of 6.50 between the markers D1S1653 and D1S1679, with an estimated 75 percent of families linked to this locus. Further mapping has reduced the interval containing this gene to less than 2 Mb. We propose a project to develop a dense map of polymorphic markers within this currently defined minimum genetic region, for use in crossover and linkage disequilibrium analyses to further narrow the region containing the gene. Using sequence data from the Human Genome Project, we then plan to identify a comprehensive list of gene in the new minimum genetic region and systematically screen them for mutations using temperature gradient gel electrophoresis on a sample of subjects with very high (greater than 95 percent) conditional probability of linkage to 1Q21-22. Simulation studies suggest that we will have sufficient power to identify the true susceptibility gene. We plan to screen this gene for mutations in the remainder of our linkage sample and in the schizophrenia subjects in the NIMH Center for Genetics Studies sample. The identification of a gene involved in schizophrenia susceptibility will allow insight into the earliest genesis of this debilitating illness. Screening for mutations in this gene in larger, unrelated samples will allow for an estimate of the prevalence of the effect of this locus in the general population. Controlling for the effects of this gene in genetic linkage studies should increase the power to identify other susceptibility loci. Unraveling the genetics of this complex disorder will also facilitate the investigation of the environmental triggers of disease expression, and could ultimately lead to strategies to prevent the onset of clinical symptoms.
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