A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia
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Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
We thank IDgene’s former employees and clinical collaborators, in particular Meira Sternfeld and Naomi Zak. We also thank Jonathan Flint and Saffron A. G. Willis-Owen for their helpful comments on the manuscript and Bening-Abu-Shach Ulli for excellent technical assistance. This study was supported in part by the Wasserman fund Tel Aviv University to Ruth Navon. Sagiv Shifman is supported by an EMBO fellowship. We would like to thank the Stanley Medical Research Institute Brain Collection, for providing tissue samples together with important data, which made this study possible. Particular thanks are to Maree Webster and her staff.
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