Analysis of dysbindin interacting genes in the pathogenesis of schizophrenia

Dysbindin (dystrobrevin-binding protein 1 DTNBP1) has been implicated as a schizophrenia candidate gene. However while numerous positive associations have been reported, no non-synonymous alleles have been found which account for the association. A number of recent studies suggest that altered dysbindin expression may be the mechanism by which DTNBP1 variants confer susceptibility to schizophrenia. Therefore one objective of this study was to identify putative DTNBP1 cis-acting variants and perform association analyses of these variants with schizophrenia and allelic expression differences observed at the DTNBP1 locus. While four variants were associated with schizophrenia, logistic regression suggested that the signal observed at these polymorphisms was not independent of the most associated SNP rs4715984. Comparison with the results of a DTNBP1 allelic expression assay revealed that seven SNPs were associated with differential expression. Post hoc analysis revealed that the majority of the expression differences were accounted for by variation at two loci (rs2619538 and rsl3198512), one of which (rsl3198512) was subsequently shown to directly affect transcription in vitro using a luciferase reporter gene assay. As rs4715984 was not correlated with allelic expression differences it implies that a reduction in dysbindin expression through cis-acting variation may not be the primary aetiological factor in schizophrenia pathogenesis. This was supported by further analysis of a schizophrenia risk haplotype previously reported to be associated with differential expression as the refined haplotype was no longer correlated. A second objective of this thesis was to investigate the hypothesis that DTNBP1 could cause susceptibility to schizophrenia through its role within the BLOC-1 complex. Association analysis was performed on BLOC-1 genes which displayed evidence of being under the influence of cis-acting regulation. MUTED, a BLOC-1 gene previously reported as associated to schizophrenia was also investigated. However association results provided no compelling support for the hypothesis that DTNBP1 contributes to susceptibility to schizophrenia through the BLOC-1 complex