Abstract
Schizophrenia is a common, complex disease with a substantial genetic component and an estimated heritability of 80%. The molecular pathology underpinning its genetic susceptibility is largely unknown. The recent genome-wide association studies (GWAS) have revealed common and rare genetic polymorphisms robustly associated with schizophrenia, giving a great boost to the field. A major challenge, which is essential for these findings to be translated into novel treatments, is to elucidate the biological mechanisms by which these genetic variants alter gene function and biological networks, the downstream effects on brain function and in turn disease risk. The main aim of thisthesis was to characterize the molecular and cellular mechanisms by which genetic variation in the loci containing the transcription factor 4 (TCF4) and vaccinia-related kinase 2 (VRK2) genes confer susceptibility to schizophrenia. The work presented in this thesis can be divided into three main modules: i) a bioinformatic module used to gather information from public database to complement our current knowledge and highlight areas of interest for further investigation; ii) knockdown of VRK2 and TCF4 mRNA in a neuronal progenitor cell line; and iii) assay of relative allelic expression of VRK2.
The findings presented in this thesis provide experimental evidence for the biological effect of TCF4 and VRK2 on cell proliferation in human neural progenitor cells in vitro, indicating this as a possible mechanism underlying the influence of these genetic variants on the pathology of schizophrenia. Additionally, allelic expression analyses revealed an effect of genotype at rs2312147 on VRK2 allelic expression in foetal samples suggesting
a molecular risk mechanism for schizophrenia operating during early brain development, long before the evident appearance of the disease.
The result presented in this thesis support the idea that schizophrenia is in part a neurodevelopmental disorder and provides new insight for molecular mechanism underlying the pathology of the disease.
| Date of Award | 2014 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Leonard Schalkwyk (Supervisor), David Collier (Supervisor) & Nick Bray (Supervisor) |