Limits of fine-mapping a quantitative trait

Once a significant linkage is found, an important goal is reducing the error in the estimated location of the linked locus. A common approach to reducing location error, called fine-mapping, is the genotyping of additional markers in the linked region to increase the genetic information. The utility of fine-mapping for quantitative trait linkage analysis is largely unknown. To explore this issue, we performed a fine-mapping simulation in which the region containing a significant linkage at a 10-centiMorgan (cM) resolution was fine-mapped at 2, 1, and 0.5 cM. We simulated six quantitative trait models in which the proportion of variation due to the quantitative trait locus (QTL) ranged from 0.20-0.90. We used four sampling designs that were all combinations of 100 and 200 families of sizes 5 and 7. Variance components linkage analysis (Genehunter) was performed until 1,000 replicates were found with a maximum lodscore greater than 3.0. For each of these 1,000 replications, we repeated the linkage analysis three times: once for each of the fine-map resolutions. For the most realistic model, reduction in the average location error ranged from 3-15% for 2-cM fine-mapping and from 3-18% for 1-cM fine-mapping, depending on the number of families and family size. Fine-mapping at 0.5 cM did not differ from the 1-cM results. Thus, if the QTL accounts for a small proportion of the variation, as is the case for realistic traits, fine-mapping has little value.