Attributing Hardy-Weinberg disequilibrium to population stratification and genetic association in case-control studies.
Loci exhibiting Hardy-Weinberg disequilibrium (HWD) are often excluded from association studies, because HWD may indicate genotyping error, population stratification or selection bias. For case-control studies, HWD can result from a genetic effect at the locus. We extend the modelling to accommodate both stratification and genetic effects. Theoretical genotype frequencies and HWD coefficients are derived under a general genetic model for a population with two strata. Maximum likelihood is used to estimate model parameters and a test for lack of fit identifies the models most consistent with the data. Simulations were used to assess the method. The technique was applied to a group of ethnically and clinically heterogeneous kidney stone formers and controls, both exhibiting HWD for the R990G SNP of the CASR gene. Results indicate the best fitting model incorporates both stratification and genetic association. The ability of our method to apportion HWD to stratification and genetic effects may well be a significant advance in dealing with heterogeneity in case-control genetic association studies.
Grover
Vaneeta K
VK
Department Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada.
Cole
David E C
DE
Hamilton
David C
DC
D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D005828:Genetics, Population / Q000379:methods; D006801:Humans; D007669:Kidney Calculi / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical