Genotype-Based Case-Control Analysis, Violation of Hardy-Weinberg Equilibrium, and Phase Diagrams

We study in detail a particular statistical method in genetic case-control analysis, labeled “genotypebased association”, in which the two test results from assuming dominant and recessive model are combined in one optimal output. This method differs both from the allele-based association which artificially doubles the sample size, and the direct χ test on 3-by-2 contingency table which may overestimate the degree of freedom. We conclude that the comparative advantage (or disadvantage) of the genotype-based test over the allele-based test mainly depends on two parameters, the allele frequency difference δ and the Hardy-Weinberg disequilibrium coefficient difference δǫ. Six different situations, called “phases”, characterized by the two X test statistics in allele-based and genotypebased test, are well separated in the phase diagram parameterized by δ and δǫ. For two major groups of phases, a single parameter θ = tan(δ/δǫ) is able to achieves an almost perfect phase separation. We also applied the analytic result to several types of disease models. It is shown that for dominant and additive models, genotype-based tests are favored over allele-based tests.