Grover Vaneeta K, Cole David E C, Hamilton David C
Department Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada.
Ann Hum Genet. 2010 Jan;74(1):77-87. doi: 10.1111/j.1469-1809.2009.00552.x. Epub 2009 Nov 20.
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.
表现出哈迪-温伯格不平衡（HWD）的基因座通常会被排除在关联研究之外，因为HWD可能表明基因分型错误、群体分层或选择偏差。对于病例对照研究，HWD可能是由该基因座的遗传效应导致的。我们扩展了模型，以同时考虑分层和遗传效应。在一个具有两个亚群的总体的一般遗传模型下，推导了理论基因型频率和HWD系数。使用最大似然法估计模型参数，并通过拟合优度检验来确定与数据最一致的模型。通过模拟评估该方法。该技术应用于一组种族和临床特征各异的肾结石患者及对照，他们对于钙敏感受体（CASR）基因的R990G单核苷酸多态性（SNP）均表现出HWD。结果表明，最佳拟合模型同时包含了分层和遗传关联。我们的方法将HWD归因于分层和遗传效应的能力，很可能是在处理病例对照遗传关联研究中的异质性方面的一项重大进展。
