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Title: Genetic association between schizophrenia and type-2 diabetes
Author: Mathur, Aditi
ISNI:       0000 0004 2707 3787
Awarding Body: University of Aberdeen
Current Institution: University of the Highlands and Islands
Date of Award: 2011
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Aims: This PhD project was designed under two studies, the genetic association study to investigate a genetic component or a genetic pathway that might be associated with both schizophrenia and type-2 diabetes (T2D). The gene functional study to explore whether clozapine could affect expression of the genes associated with obesity and T2D. Methods: In genetic association study, a total of 17 single nucleotide polymorphisms (SNPs) were genotyped in the PPARG, PLA2G4A, PTGS2 and AKT1 genes in 221 British nuclear families. In the gene functional study, U937 cells were treated with clozapine (1g/ml and 2g/ml) for 48 hours and 96 hours. Quantitative real-time PCR analysis was used to measure the mRNA expression levels of the genes of interest in clozapine-treated and untreated cells. Results: Eight SNPs tested across the PPARG gene did not show allelic association with schizophrenia. An association was detected at rs2745557 in the PTGS2 locus (2=4.19, p= 0.041) and rs10798059 in the PLA2G4A locus (2=4.28, p=0.039), but these associations did not survive after 10,000 permutations (global p=0.246). Allelic association for the AKT1 gene was detected at rs1130214 (2=6.28, p=0.012) and at rs11847866 (2=4.64, p=0.031) only although the global p-value of overall associations for the AKT1 was 0.059 after 10,000 permutations. Haplotype analysis showed a disease association for the rs1130214-rs2494746-rs11847866 haplotypes (2= 10.18, df= 4, p=0.037), of which the T-G-A haplotype was excessively transmitted (2=6.93, p=0.008) and this haplotypic association survived the Bonferroni correction (p=0.04). The expression of the MTCH2 gene showed a significant decrease in mRNA expression (combined p=0.001) and that of the PPARG gene showed a significant increase (combined p=0.005) in the cells treated with 1g/ml clozapine for 96 hours. Conclusions: The present results support the AKT1 gene association with schizophrenia as reported in previous studies; both the MTCH2 and PPARG genes may be involved in the development of clozapine-induced obesity and in an increased risk of T2D.
Supervisor: Wei, Jun ; Megson, Ian ; Law, Matthew Sponsor: SAGB
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Diabetes Mellitus, Type 2 ; Schizophrenia