Molecular analysis of schizophrenia by the integrated approach

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1.Linkage studies : The first genome-wide scan using 417 STR markers in 130 families with affected sib-pairs revealed that ten chromosomes (1,2,3,4,5,8,9,14,17, and 20) had at least one region with a nominal p value <0.05. The second genome-wide scan using 5,861 SNPs in 236 Japanese families including 122 ones used in the first scan revealed that significant evidence of linkage of schizophrenia to 1p21.1-1p13.1 and suggestive evidence of linkage to 14q11.2, 4q11.2-q13.2 and 20p12.1-p11.2.2.Association studies : Based on the glutamatergic dysfunction hypothesis for the pathogenesis of schizophrenia, we conducted. a systematic study of associations between glutamate receptor genes and schizophrenia. We selected SNPs evenly distributed across the relevant gene regions for single marker and haplotype association studies. We found significant associations of haplotypes of GRIN2D, GRIA4, GRM3 and GRM8 with schizophrenia. Genome-wide association study using 27,000 STR markers is on the way. The second set of screening showed significant associations of 720 markers with schizophrenia. The third and fourth sets of screening followed by dense SNP typing will elucidate the susceptibility loci for schizophrenia.3.Model animal-based studies :(i)PCP is known to cause schizophrenia-like symptoms in human and animals, providing a well-suited model for schizophrenia. We screened the PCP-responsible genes by the microarray-based procedure using brain samples of PCP- administrated rats. We selected 10 genes differentially expressed at the level of more than 2.5 folds due to the PCP treatment. We are now doing association study of these genes with schizophrenia.(ii) To evaluate the involvement of GRIA4 in pathogenesis of schizophrenia, we generated GluR4 deficient mice by the homologous recombination technique. Heterozygous and homozygous mutant mice were born alive, appeared normal, and were fertile in adult. For behavioral examination, a 129/sv x C57BI/6J backcross is under way.