Molecular Genetics of Schizophrenia Susceptibility

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DESCRIPTION (provided by applicant): Schizophrenia is a serious neuropsychiatric illness estimated to affect approximately 1% of the general population. Family, twin and adoption studies have demonstrated that schizophrenia is predominantly a genetic disorder, with a high heritability. Segregation analyses have failed to clearly support a single model of inheritance and suggest at least several, possibly interacting, susceptibility loci. We have previously identified a strong linkage signal (hlod=6.5, empirical p less than 0.0002) to 1q22 in a set of medium-sized Canadian families, selected for study because multiple relatives were clinically diagnosed with schizophrenia or schizoaffective disorder. Fine-map linkage analysis has identified an approximately 1.3 Mb interval that appears very likely to harbor the susceptibility gene, with a 300 kb sub-region identified by linkage as most likely to contain the gene. We have further identified significant linkage disequilibrium (LD) within a 100 kb portion of this sub-interval. The region of LD is contained within the over 300 kb genomic extent of the gene ICAPON, and there is evidence that additional genes may exist within the introns of this large gene. We plan to search this region for additional transcribed sequences to screen for variants associated with schizophrenia susceptibility. We also plan to use comparative genomic techniques to identify conserved regulatory regions within this area. These will also be assessed for variation that is associated with schizophrenia susceptibility. The sample with strong linkage to this region will first be tested for LD, with the NIMH-HGI collection and a Canadian case-control sample also genotyped with markers producing significant LD in the linkage sample. We also plan to conduct expression studies of protein and RNA, using RNA from the Stanley Array Collection, post-mortem brains from the Harvard Brain Bank, and lymphoblastoid cell lines from our linkage sample and the NIMH-HGI collection. We hope to use our investigations of this locus in this sample as a testbed for refining a comprehensive approach to susceptibility gene identification, combining linkage and linkage disequilibrium mapping, evolutionary based sequence comparison methods, and complementary gene expression studies. We anticipate that these methods will be of future use for finding additional susceptibility genes for schizophrenia and other complex disorders.