Bias of allele-sharing linkage statistics in the presence of intermarker linkage disequilibrium.

Current genome-wide linkage-mapping single-nucleotide polymorphism (SNP) panels with densities of 0.3 cM are likely to have increased intermarker linkage disequilibrium (LD) compared to 5-cM microsatellite panels. The resulting difference in haplotype frequencies versus that predicted may affect multipoint linkage analysis with ungenotyped founders; a common haplotype may be assumed to be rare, leading to inflation of identical-by-descent (IBD) allele-sharing estimates and evidence for linkage. Using data simulated for the Genetic Analysis Workshop 14, we assessed bias in allele-sharing measures and nonparametric linkage (NPL all) and Kong and Cox LOD (KC-LOD) scores in a targeted analysis of regions with and without LD and with and without genes. Using over 100 replicates, we found that if founders were not genotyped, multipoint IBD estimates and delta parameters were modestly inflated and NPL all and KC-LOD scores were biased upwards in the region with LD and no gene; rather than centering on the null, the mean NPL all and KC-LOD scores were 0.51 +/- 0.91 and 0.19 +/- 0.38, respectively. Reduction of LD by dropping markers reduced this upward bias. These trends were not seen in the non-LD region with no gene. In regions with genes (with and without LD), a slight loss in power with dropping markers was suggested. These results indicate that LD should be considered in dense scans; removal of markers in LD may reduce false-positive results although information may also be lost. Methods to address LD in a high-throughput manner are needed for efficient, robust genomic scans with dense SNPs.