Effect of linkage disequilibrium between markers in linkage and association analyses

Contributions to Group 17 of the Genetic Analysis Workshop 15 considered dense markers in linkage disequilibrium (LD) in the context of either linkage or association analysis. Three contributions reported on methods for modeling LD or selecting a subset of markers in linkage equilibrium to perform linkage analysis. When all markers were used without modeling LD, inflated evidence for linkage was observed when parental genotypes were missing. All methods for handling LD led to some decreased linkage evidence. Two groups performed a genome-wide association scan using either mixed models to account for known or unknown relatedness between individuals, trend tests or combination statistics. All methods failed to detect four of the eight simulated loci because of low LD in some regions. Three groups performed association analysis using simulated dense markers on chromosome 6, where a simulated HLA-DRB1 locus played a major role in disease susceptibility along with two additional loci of smaller effect. The overall conditional genotype method correctly identified both additional loci while a novel transmission disequilibrium test-statistic to combine studies with non-overlapping markers identified one HLA locus after stratifying on the parental HLA-DRB1 genotypes; LD mapping using the Malécot model mapped two loci in this region, even when using greatly reduced marker density. While LD between markers appears to be a nuisance that may cause spurious linkage results with missing parental genotypes in linkage analysis, association analysis thrives on LD, and disease genes fail to be detected in regions of low LD.