Correlation-based inference for linkage disequilibrium with multiple alleles

The correlation between alleles at a pair of genetic loci is a measure of linkage disequilibrium. The square of the sample correlation multiplied by sample size provides the usual test statistic for the hypothesis of no disequilibrium for loci with two alleles and this relation has proved useful for study design and marker selection. Nevertheless, this relation holds only in a diallelic case, and an extension to multiple alleles has not been made. Here we introduce a similar statistic, R-z, which leads to correlaiton -based test for loci with multiple alleles: for a pair of loci with k and m alleles, and a sample of n individuals, the approximate distribution of n(k-1) (m-1)/(km)R-2 under independence between loci is chi(2)((k-1)(m-1)). One advantage of this statistic is that is can be interpreted as the total correlation between a pair of loci. When the phase of two-locus genotypes is know, the approach is equivalent to a test for the overall correlation between rows and columns in a contingency table. In the phase-known case, R-2 is strong competitor to approaches such as Pearson's chi square, Fisher's exact test, and a test based on Cressie and Read's power divergence statistic. We combine this approach with our previous composite-disequilibrium measures to address the case when the genotypic phase is unknown. Calculation os the new multiallele test statistic and its P-value is very simple and utilizes the approximate distribution of R-2. We provide a computer program that evaluates approximate as well as "exact" permutational P-values.