This revised application for an Independent Scientist Award (K02) is focused on the genetic epidemiology of schizophrenia. Identified genetic factors of etiological importance will be examined in conjunction with non-genetic risk factors for schizophrenia Initially, it is proposed to test-I association of schizophrenia with the HLA DQB1 locus using family based studies. This locus was identified by the applicant in four independent case control studies and lies within the region of interest on chromosome 6p identified by other groups. Interactions between this putative susceptibility gene and other environmental risk factors will then be examined. Next, the role of selected 'candidate' genes will be investigated, followed by a genome wide scan to identify other regions of susceptibility. 1. Replicative studies of the original association at the HLA DQB1 locus using family based studies. 2. Refinement of the association using genetic markers flanking the HLA DQB1 locus and examination of possible associations at the sub-syndromal level. 3. Analysis of risk conferred by alleles of the HLA DQBI gene (or a linked gene with stronger association) in conjunction with known risk factors, including putative viral etiological agents. 4. Identification of other susceptibility genes and investigation of gene-environment interactions using the paradigm for the HLA DQB 1 locus. Using a training award from NIMH, the applicant initiated ascertainment of samples locally and internationally for association and linkage studies. The samples will be enlarged. The applicant has received training in basic molecular genetic and statistical techniques. The present proposal will be used as a vehicle for further training in related areas. The specific etiology of schizophrenia, a common, devastating illness is unknown. Since a significant genetic predisposition is well established, identification of predisposing genetic factors is feasible. Such information, in conjunction with non-genetic risk factors may help identify individuals at increased risk and thus enable prevention.
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