Identification of susceptibility genes for psychiatric diseases on chromosome 18

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The pericentromeric region of chromosome 18,especially 18p11.2,is described as a schizophrenia susceptibility locus. We had previously cloned two novel brain-derived transcripts from this region : the gene for a second human myo-inosititol monophosphatase (IMPA2) and a gene of unknown function, C18orf1.We performed a family-based LD study as the first step towards identifying relevant genetic loci around 18p11.2,and then followed up using a case-control approach. These markers covered 18p11.2 at an average density of 1/280 kb. A follow-up study of independent schizophrenics (n=214) and controls (n=313), revealed a significant association between the haplotype constructed by the D18S852 and 6409T>C and schizophrenia (P=0.00001).In addition, we have performed a genome-wide LD survey of susceptibility loci for schizophrenia. We first typed 119 schizophrenic pedigrees (357 individuals) using 444 microsatellite markers. This analysis revealed 14 markers demonstrating significant transmissio … More n distortion. We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P=0.00005,global P=0.022). However, further support for chromosome 18 was not obtained by transmission distortion analysis.Besides, we have genotyped 496 Japanese bipolar patients and 543 control subjects, using 17 SNPs on and around the IMPA2 gene. The distributions of haplotypes defined by -1051G>T,-708G>A,-461C>T and IVS1+1801C>T were different between control and schizophrenia groups (P=0.007). These findings suggest that the IMPA2 gene or a gene nearby may contribute to the overall genetic risk for bipolar disorder. Recently, we set out an in-vitro assay of the gene to reveal an influence of the SNPs on transcriptional activity. The present study should be expanded upon at increased marker resolution, followed by replication and confirmation tests in different sets of larger samples. Less