Date of Award
2008
Degree Type
Thesis
Degree Name
Doctor of Philosophy
Program
Biology
Supervisor
Dr. Shiva Singh
Second Advisor
Dr. Anthony Percival-Smith
Third Advisor
Dr. Sashko Damjanovski
Abstract
Schizophrenia and affective disorder are common, related mental disorders. They are episodic or chronic in nature and first present between adolescence and adulthood. The symptoms of the two diseases are variable, overlap and include mania, depression, delusions, hallucinations and disorganization of speech and behaviour. Treatments for both diseases include antidepressants and antipsychotics, but there are no cures. Both are thought to be neurodevelopmental in nature and family studies have demonstrated strong genetic components. The search for these genetic components has identified a number of genomic regions and candidate genes but no causal gene. Ofthese genomic regions, both the long and short arm of chromosome 6 have consistently produced positive associations. This study was undertaken to examine the possible contribution of two candidate genes from chromosome 6 to schizophrenia and affective disorder, the serotonin 1B gene (HTRIB) from 6ql3 and NOTCH4 from 6p21.3. HTR1B is considered a candidate due to its autoregulatory role in the serotonin system while NOTCH4 is considered due to the neurodevelopmental nature of the diseases and the role it plays during brain development. Schizophrenia studies on the two genes involved the association of SNPs in a casecontrol study representing a sample from Southwestern Ontario and methylation analysis of the translational start using sodium bisulfite (which also included 31 regions of a human brain). The affective disorder studies on the two genes examined the same SNPs and methylation in an extended family. The results indicated that none of the 14 polymorphisms from HRTlB or NOTCH4 were associated with schizophrenia in the case-control sample. Further, these iii polymorphisms showed no association with affective disorder in the family based studies. Methylation analysis indicated that the translational start of HTRIB was completely unmethylated in the blood of all control and affected individuals for both diseases. NOTCH4 translational start analysis showed variable/partial methylation at -25C in both schizophrenia and affective disorder samples but was not associated to either disease. Variable/partial methylation was also observed at -25C in different brain regions which are known to have different levels of NOTCH4 expression.
Recommended Citation
McDonald, Patrick Peter, "SINGLE NUCLEOTIDE POLYMORPHSIM AND METHYLATION ANALYSIS OF HTR1B AND NOTCH4 IN SCHIZOPHRENIA AND AFFECTIVE DISORDER" (2008). Digitized Theses. 4575.
https://ir.lib.uwo.ca/digitizedtheses/4575