Linkage analysis can be problematic when applied to the multifactorial disease of schizophrenia. Obstacles to the success of linkage analysis include genetic heterogeneity, reduced penetrance, paucity of large multiplex families, difficulty in disease diagnosis in relatives, the possibility of phenocopies, and the possibility that misspecification of the genetic model may strongly affect the results of multipoint linkage. RFLP-based case-control association studies also may be problematic because they rely both on linkage between the RFLP and the causative mutation(s) as well as on linkage disequilibrium between the RFLP marker and the causative mutation(s). With the advent of the polymerase chain reaction (PCR) and adjunct methodology, another approach to elucidating the genetic predisposition to schizophrenia has become possible. The approach is two-tiered and first involves the identification in candidate genes of DNA sequence variations that produce structural alterations in the protein or affect the consensus segments that regulate the level of gene expression. Many of these variations will be of functional significance. Such sequence variations can be detected by direct genomic sequencing or by screening with other PCR-based methodologies such as single strand conformation polymorphism analysis in a sample of schizophrenics. Once a sequence variation of likely functional significance is found in a candidate gene, the prevalence of that allele is compared in a large group of unrelated schizophrenic cases and ethnically-similar controls to determine if a disease association exists. We have established a DNA bank on nearly 500 DSM-III-R defined schizophrenics and 1200 controls and have tested two candidate genes for an association with schizophrenia. Herein, we propose to: 1) expand the study sample to 900 cases and 1800 controls; 2) partially test the dopamine and norepinephrine hypotheses of schizophrenia by searching for sequence variants of likely functional significance in at least 15 candidate genes in the """"""""catecholamine system"""""""" and testing any such variants for disease associations in the case-control sample; and, 3) develop methodology for rapidly and accurately detecting single basepair changes in candidate genes.
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