Identification of susceptibility genes for functional psychoses by whole genome scan

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Family-based linkage disequilibrium (LD) mapping has been suggested as a powerful and practical alternative to linkage analysis. We have performed a genome-wide LD survey of susceptibility loci for schizophrenia in a Japanese population. We first typed 119 schizophrenic pedigrees (357 individuals) with 444 microsatellite markers, and analyzed the data using the pedigree disequilibrium test. This analysis revealed 14 markers that showed significant transmission distortion. To corroborate these findings, we changed our statistical methods to the extended transmission disequilibrium test (ETDT) , using 80 independent complete trios (a schizophrenic offspring and their parents), 68 of which were derived from the initial pedigrees and 12 newly recruited trios. ETDT supported two markers for continued association, D11S987 on 11q13.3 (P=0.00009) and D16S423 on 16p13.3 (P=0.002). We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Results of three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P=0.0005, global P=0.022). Although the present study may have missed other potential genomic intervals because of the sparse mapping density, we hope that it has identified promising anchor points for further studies to identify risk-conferring genes in Japanese schizophrenia.