Novel schizophrenia risk genes and gene expression

ZNF804A was (at the time this work started) one of only a few robustly implicated schizophrenia susceptibility genes, due to replicated genome-wide significant evidence for association between a polymorphism in the gene and schizophrenia. Determining the function of the ZNF804A protein, which is currently unknown, may provide a way of elucidating the pathophysiology of this relatively common, complex disorder. Based on the hypothesis that the ZNF804A protein regulates gene expression or splicing, the aim of this thesis was to identify genes that exhibit altered expression or splicing in brain tissue from mice in which the orthologue Zfp804a carries a nonsense mutation. No robust evidence was obtained that showed the effects of the mutation on differential expression in individual genes. Although this finding does not support the hypothesis that ZNF804A acts directly to regulate gene expression, the results may reflect the possibility that effects on gene expression may be too subtle to be detected using the methods applied. Evidence was obtained to show the mutation affected the alternative splicing of a number of individual genes, which could suggest a role for ZNF804A in the direct or indirect regulation of alternative splicing. Through RNA sequencing, I identified a novel transcript in Zfp804a with an alternative exon upstream of the Refseq exon 1. I also showed that a proportion of the significant splicing differences identified in mutants were artefacts of strain differences in gene sequences that are likely to affect the efficiency of hybridisation on the exon array. Genes identified as differentially spliced between mutants and wildtypes were enriched in axon guidance and cell adhesion pathways, both thought to be important during development. The findings of this thesis suggest the novel hypothesis that ZNF804A effects risk for schizophrenia via aberrant splicing in the above pathways that are critical to normal brain development. Further studies with increased power are required to understand the effects on gene expression