The effects of linkage disequilibrium in large scale SNP datasets for MDR

Four relative amounts of LD were simulated in multiple one- and two-locus scenarios for which the position of the functional SNP(s) within LD blocks varied. Simulated data was analyzed with MDR to determine the sensitivity of the method in different contexts, where the sensitivity of the method was gauged as the number of times out of 100 that the method identifies the correct one- or two-locus model as the best overall model. As the amount of LD increases, the sensitivity of MDR to detect the correct functional SNP drops but the sensitivity to detect the disease signal and find an indirect association increases.Higher levels of LD begin to confound the MDR algorithm and lead to a drop in sensitivity with respect to the identification of a direct association; it does not, however, affect the ability to detect indirect association. Careful examination of the solution models generated by MDR reveals that MDR can identify loci in the correct LD block; though it is not always the functional SNP. As such, the results of MDR analysis in datasets with LD should be carefully examined to consider the underlying LD structure of the dataset.Linkage disequilibrium (LD) is defined as the nonrandom association of alleles at two or more loci [1]. The concept of LD and the statistics used to measure it relate directly to the frequency of ancestral recombination events which have separated the loci between which calculations are made. Frequent recombination between loci of genetic variation will result in linkage equilibrium. Thus it is often the case that when there is LD, it is due to physically linked genetic variants. LD can also result from population genetic events such as admixture and natural selection. GWAS take advantage of LD to be able to identify indirect associations but also suffer from strong LD over large genomic regions. The problem with LD in genomic data and its ability to confound analysis is illustrated by the human leukocyte antigen (HLA) locus, which was at t