The previous grant MH44212 supported the ascertainment and phenotyping of seventeen multiplex pedigrees and it provided monies for genotyping and linkage analyses. In addition to meeting the primary goals of the original grant, we carried out simulation runs to evaluate the power of the pedigree sample for linkage analysis, genotyped nine pedigrees with over 329 DNA markers and performed linkage analyses. To date, strong evidence of linkage has not been found with these DNA markers, including probes which define the D1, D2, D3, D4, and D5 dopamine receptor genes. The primary goal of the proposed grant renewal is to test the hypothesis that a major genetic locus underlies schizophrenia in a subgroup of families. The will be carried out by: 1. Enlarging our sample of 17 current pedigrees to 25 moderately sized, high density families to increase power to detect linkage. 2. A two-pronged genotyping approach. The schizophrenic pedigrees will be genotyped using a. Polymorphic candidate genes implicated in the pathophysiology of schizophrenia. b. A linkage map with simple sequence repeat (SSR) markers spaced at 5 centimorgan intervals. 3.The lod score method as well as the affected pedigree member method of linkage analysis. 4. Analysis of two neurophysiological variables, the P50 evoked auditory response and SPEM, in addition to analysis using the schizophrenia phenotype. 5. Linkage analysis with brain cDNA's that contain highly informative polymorphic microsatellite sequences. 6. Mutation scanning techniques in candidate genes that map to promising areas of linkage. 7. Use of the approaches described above to search for linkage in large pedigrees on the Micronesian island, Palau.
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