An Examination of Hardy-Weinberg Disequilibrium and Statistical Testing in Genetic Association Studies
Date
2010-06-30
Authors
Grover, Vaneeta Kaur
Journal Title
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Abstract
In an unpublished study in Toronto it was observed that cases were in Hardy-Weinberg Equilibrium at a locus whereas their family members were in Hardy-Weinberg Disequilibrium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.
Description
Departure 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In an unpublished study in Toronto it was observed that cases were in Hardy-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.
Keywords
Hardy-Weinberg equilibrium, Stratification, Relative pairs, discordant pairs, association studies, likelihood