How useful is the fine-scale mapping of complex trait linkage peaks? Evaluating the impact of additional microsatellite genotyping on the posterior probability of linkage.

The two-stage linkage mapping protocol for complex traits (a primary genome scan with low marker density followed by the high-density genotyping around linkage peaks) is a near-universal practice. The behavior (an increase or a decrease) of the peak upon such fine mapping frequently leads to inferences regarding the veracity of the primary scan finding, namely a true, or a false, positive. We examined by simulation, under the null hypothesis of no linkage and the alternative hypothesis of true linkage, the inferences that can be made regarding the posterior probability of linkage given either a peak increase, or alternatively, a peak decrease, following fine mapping. We considered different models of missing genotype data, fine-mapping LOD score thresholds, and prior probabilities of linkage. Our simulations show that evidence for linkage can increase frequently upon fine mapping under both null and alternative hypotheses, although large increases in LOD scores are more common under the alternative hypothesis. Increased LOD scores accompany an increased posterior probability of linkage, and large LOD score changes and the presence of dominance at the trait locus accentuate this effect. We demonstrate that the greatest changes in the posterior probability of linkage occur when the genotyping data are least complete (and especially when parental genotypes are missing), and the LOD score threshold for fine mapping is relaxed. 2004 Wiley-Liss, Inc.