Several chromosomal loci obtained from genetic linkage studies have been reported of relating to schizophrenia. These areas include of 1q32-41, 6p24-21, 8p22-21, 15q13-14, and 22q11-12. The names of these genes located in these loci have not been identified, nor have the function and the relationship to the disease. Our research team using genetic linkage studies has found a strong linkage (NPL Z score = 2.18, p=0.01) between the D1S251 marker and schizophrenia disease. This marker is about 4 kb away from DISC1 (disrupted in schizophrenia gene 1) gene. In a Scottish family, a balanced translocation [t(1;11) (q42.1;q14.3)] has cosegregated inside the schizophrenia affected members of the family (LOD score =6.0). The breakpoint of the translocation is located at the intron area between exon 8 and exon 9 of DISC1 gene. This translocation disrupted the gene and caused its malfunction. A large molecular genetic study study recently in Finland has also demonstrated strong linkage evidence (Zmax=3.21) between the DIS2709 marker, located among exon 4 and exon 5 of DISC1 gene, and schizophrenia in a. All these findings have indicated that DISC1 gene is a potential positional candidate gene and worth for further study.

The main purposes of this proposal include: (1) To evaluate the incidence rate of the balanced translocation between the chromosome 1q42.1 and 11q14.3 in approximately 500 schizophrenic patients in Taiwan. Furthermore, we will compare the clinical symptoms, illness course, and family genetic model to examine if any particular characters coexist with the translocation. (2) To search for the genetic polymorphisms in DISC1 gene area, where the thirteen exons, the promoter regions (1 kb upstream the start codon), and the breakpoint area (1 kb of both upstream and downstream area) will be analyzed by the method of denaturing high performance liquid chromatography (DHPLC). Case-control association study will be performed further in each 200 schizophrenic patients and normal controls to evaluate the relationship between the disease and the clinical characteristics.

This proposal is quite feasible and prospective with the following reasons. (1) All the DNA samples and the clinical data have been collected and evaluated completely for further analysis. (2) Our research team has built up an integrated andreliable molecular genetic laboratory. All the facilities necessary for this study (DHPLC) had been setup with standard operating protocols and working routinely. (3) DISC1 gene has strong linkage evidence with schizophrenia in Taiwanese sample. The high prior probability of DISC1 gene as a positional candidate gene increases the successfulness of association study. . (4) Once the relationship among balance translocation, genetic polymorphism and the schizophrenia have established, further functional study will be evaluated to understand the possible mechanisms involved in the disease.