Genomic and functional analysis of dysbindin in the genesis of schizophrenia. (360G-Wellcome-077693_Z_05_Z)

Strong evidence now implicates DTNBP1 as a susceptibility gene for schizophrenia. However its pathogenic role remains unclear. We aim to translate this strong genetic evidence to a real understanding of pathogenesis by first identifying the specific genetic variants at DTNBP1 responsible for reported haplotypic associations with schizophrenia and then determining their effect upon DTNBP1 function. To achieve this, DTNBP1 will be re-sequenced and all DNA variants genotyped in our large sample of 860 cases and 860 matched controls. Positive associations will be replicated in two independent samples of 219 Irish cases and 231 matched controls and 600 Bulgarian parent-proband trios. The pathological mechanism of these DTNBP1 risk variants will then be established via functional genomic methodologies. This proposal also aims to establish whether any of the genes encoding proteins functionally related to dysbindin themselves confer susceptibility to schizophrenia. We will identify known and novel proteins from the literature and via immunoprecipitation assays respectively, that interact with dysbindin and then seek associations between schizophrenia and variations in the genes that encode the dysbindin interacting proteins. This will establish which dysbindin related mechanisms are involved in the pathogenesis of schizophrenia, improving our understanding of the origins of this disorder.