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dc.contributor.authorGrover, Vaneeta Kaur
dc.date.accessioned2010-06-30T15:01:55Z
dc.date.available2010-06-30T15:01:55Z
dc.date.issued2010-06-30
dc.identifier.urihttp://hdl.handle.net/10222/12845
dc.descriptionDeparture from HWE (HWD) in a sample may indicate genotyping error, population stratification, selection bias, or some combination thereof. Therefore, loci exhibiting HWD are often excluded from association studies. However, it has been shown that in case-control studies HWD can result from a genetic effect at the locus, and HWD at a marker locus can be interpreted as evidence for association with a disease. In an unpublished study in Toronto it was observed that cases were in Hardy- Weinberg equilibrium at a locus whereas their family members were in HWD. It has been shown that the HWD coefficient for a multiplicative genetic model is zero. This led to an investigation of relatives of affected individuals to see whether the multiplicative model could be revealed by a nonzero HWD coefficient in relatives. Genotypic frequencies and HWD coefficients were derived for affected individuals and their affected and unaffected relatives. A substantial HWD was found in both individuals in dominant and recessive genetic models but HWD is only slightly nonzero for additive and multiplicative models. Methods were also developed to test for association using data from affected individuals and their relatives. Parameter estimates for these models can be obtained using maximum likelihood methods, and estimates provide valuable information regarding the mode of inheritance of the disease. The methods were applied to 112 discordant sib pairs with Alzheimer’s disease typed for the ApoE polymorphism and a significant association was observed between the "4 ApoE allele and Alzheimer’s disease. Case-control studies may indicate spurious association with a marker locus in a stratified population. Methods were developed to determine if the HWD observed in a data set from a stratified population can be explained by both genetic association and stratification. Parameter estimates for these models can be obtained using maximum likelihood methods, and used to deduce the mode of inheritance of the disease. Applying the model to the R990G SNP of the CASR gene, it was found that the HWD was adequately explained by a recessive genetic association and a stratification proportion of 10%, consistent with the population of Toronto.en_US
dc.description.abstractIn an unpublished study in Toronto it was observed that cases were in Hardy-Weinberg Equilibrium at a locus whereas their family members were in Hardy-Weinberg Disequilibrium (HWD). This led to an investigation of relatives of affected individuals to see whether the multiplicative model could be revealed by a nonzero HWD coefficient in relatives. Genotypic frequencies and HWD coefficients were derived for affected individuals and their affected and unaffected relatives. Methods were also developed to test for association using data from affected individuals and their relatives. In addition, a model was developed to assess whether the HWD observed in a data set from a stratified population can be explained by both genetic association and stratification. Parameter estimates for these models can be obtained using maximum likelihood methods, and used to deduce the mode of inheritance of the disease.en_US
dc.language.isoenen_US
dc.subjectHardy-Weinberg equilibrium, Stratification, Relative pairs, discordant pairs, association studies, likelihooden_US
dc.titleAn Examination of Hardy-Weinberg Disequilibrium and Statistical Testing in Genetic Association Studiesen_US
dc.date.defence2010-06-18
dc.contributor.departmentDepartment of Mathematics & Statistics - Statistics Divisionen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerDr. J Concepcin Loredo-Ostien_US
dc.contributor.graduate-coordinatorDr. Ed Suskoen_US
dc.contributor.thesis-readerDr. Chris Fielden_US
dc.contributor.thesis-readerDr. Bruce Smithen_US
dc.contributor.thesis-supervisorDr. David Hamiltonen_US
dc.contributor.ethics-approvalNot Applicableen_US
dc.contributor.manuscriptsYesen_US
dc.contributor.copyright-releaseYesen_US
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