Mathematical properties of the r2 measure of linkage disequilibrium

摘要

Statistics for linkage disequilibrium (LD), the non-random association of alleles at two loci, depend on the frequencies of the alleles at the loci under consideration. Here, we examine the r² measure of LD and its mathematical relationship to allele frequencies, quantifying the constraints on its maximum value. Assuming independent uniform distributions for the allele frequencies of two biallelic loci, we find that the mean maximum value of r² is ~0.43051, and that r² can exceed a threshold of 4/5 in only ~14.232% of the allele frequency space. If one locus is assumed to have known allele frequencies – the situation in an association study in which LD between a known marker locus and an unknown trait locus is of interest – we find that the mean maximum value of r² is greatest when the known locus has a minor allele frequency of ~0.30131. We find that in 1/4 of the space of allowed values of minor allele frequencies and haplotype frequencies at a pair of loci, the unconstrained maximum r² allowing for the possibility of recombination between the loci exceeds the constrained maximum assuming that no recombination has occurred. Finally, we use rmax2 to examine the connection between r² and the D′ measure of linkage disequilibrium, finding that r2/rmax2=D′2 for ~72.683% of the space of allowed values of (pa, pb, pab). Our results concerning the properties of r² have the potential to inform the interpretation of unusual LD behavior and to assist in the design of LD-based association-mapping studies.