Genetic variants and gene expression in schizophrenia

grantor: University of TorontoThe objective of my Ph.D. research was to identify genetic variations which could underlie or contribute to schizophrenia. To achieve this goal, I have undertaken two approaches. Since an abnormality of the dopaminergic system has been proposed as being central to the pathophysiology of schizophrenia, my initial approach was to screen for variations in genes encoding known dopamine receptors in schizophrenics, and to clone novel dopamine receptor(s). This approach led to the identification of a dopamine D4 receptor variant, termed D4Valine194Glycine, in African descendants. One individual that was homozygous for this mutation was also identified. Further studies showed that the ability of this naturally occurring mutant receptor to bind dopamine was severely reduced. Genetic association studies revealed, however, that the D4Valine194Glycine variant was not related to susceptibility to schizophrenia. In addition, the association of a dopamine D2 receptor polymorphism (D2-141C 'Del') with schizophrenia was examined in our patient samples; this study likewise demonstrated no significant correlation. An attempt to isolate new dopamine receptor(s) resulted only in the identification of a novel G protein coupled receptor pseudogene. Since previous studies have suggested the contribution of altered gene expression to psychiatric diseases, I hypothesized that alterations in the expression of certain genes in the schizophrenic brain could lead to its diseased state. My second approach, therefore, was to compare the gene expression pattern of schizophrenic brains with that of controls using postmortem striata and mRNA differential display. Using this approach, a novel transcript (clone 19) was identified. The transcript corresponding to clone 19 was subsequently found to be significantly underrepresented in schizophrenic brains. Its deficit may be causative to the disease or it may be disease-induced.Ph.D