Project Summary

David Valle, M.D. (Distinguished Investigator 2007) of Johns Hopkins School of Medicine, plans to perform detailed studies on two genes, GRID1 and NRG3, which he recently has found may play a role in schizophrenia. He has recently studied a well-characterized population of Ashkenazi Jewish families that has 300 people with schizophrenia. Using the population, he completed a genome-wide linkage study that yielded a strong linkage signal over a 12.5 Mb region at 10q22, which was replicated in a subsequent genome-wide candidate gene SNP association study showing significant or near significant association for variants in and around two genes (GRID1 and NRG3) located 2.5 Mb apart in the 10q22 region. These genes are both excellent schizophrenia candidates. Why? GRID1 encodes a member of the glutamate receptor family and recent unpublished information from groups in Finland and China replicates their association results. NRG3 encodes an integral membrane protein highly expressed in the CNS whose cytoplasmic domain is cleaved and interacts with ErbB 4 receptors. Another member of the NRG family (NRGI) also has been strongly implicated in schizophrenia. It is possible both genes contribute to schizophrenia risk, thus explaining the strong linkage signal we observed for this region. Finally, Dr. Valle et al obtained (117kb) fine mapping of 1449 SNPs in the region in 1,771 individuals (478 patients, 531 controls, 762 relatives) and analyzing the data. Dr. Valle how seeks NARSAD funds to follow up these studies by 1) sequencing the exons, flanking intronic splice sites and conserved non-coding containing putative regulatory sequences in the large surrounding gene deserts of the two best candidate genes in our region (GRID1 and NRG3), in 25 probands and 25 controls; 2) developing detailed knowledge of the expression pattern and alternative splicing of these two candidates in regions of the brain; 3) evaluating of potentially significant SV in functional assays; and, 4) developing conditional targeting constructs to develop mouse models for these two candidates.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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