Molecular characterization of three mental illness susceptibility genes

Bipolar disorder and schizophrenia are devastating mental disorders which share an overlapping constellations of symptoms, most notably the presence of psychosis. Overlapping genetic factors are involved in their pathogenesis and recently, genome-wide linkage scans and association studies have identified many new genes. However, studies focusing on functional follow-up for these genes are very rare, leaving a big gap in comprehending how these genes contribute to the risk of illness. The goals of this thesis were to focus on three candidate genes: NRG1, ST8SIA2 and NCAM1, each associated with psychotic mental illness, and determine how these genes could be functionally involved in disease susceptibility. Working with case-control cohorts, analysis of the target genes was undertaken at the DNA, RNA and protein levels to identify possible variation, examine its potential functional impact and identify any alteration in normal activity which may affect disease status. The results from this thesis have provided a distinctive contribution to the knowledge about the mechanisms of risk provided by three candidate genes. Using this candidate gene approach, a novel schizophrenia risk mechanism was identified in which the well-known schizophrenia-associated haplotype âHAPICEâ was coupled with increased NRG1 type III expression and high nucleotide diversity in an Australian cohort (Chapter 3). In addition, several novel splice isoforms of ST8SIA2 were identified that could have a significant role in determining the functions of this candidate gene (Chapter 5). Analysis of protein expression identified an increase in the non-glycosylatable form of NCAM1 (120kDa), and a corresponding decrease in the glycosylatable NCAM1 isoforms and glycosylated NCAM (PSA-NCAM) in the dorsolateral prefrontal cortex of female schizophrenia patients (Chapter 4). A decrease in PSA-NCAM, caused by either a deficit in ST8SIA2 function or by reduced substrate availability through modulation of NCAM1, could affect axon migration and synaptic plasticity, therefore resulting in brain defects associated with psychotic mental illness.This thesis illustrates the importance of functionally characterizing candidate genes informed from gene mapping studies, particularly those that may have weaker evidence in the GWAS data due to heterogeneity (allelic, locus and phenotypic) but may still have a neurobiological impact on disease pathogenesis in specific individuals