Exploring the dense mapping of a region of potential linkage in complex disease: An example in multiple sclerosis

In 1996 we reported the results of a genome screen in multiple sclerosis, i n which potential linkage was identified in a total of twenty regions, incl uding the centromeric region of chromosome 5. In order to investigate the e fficiency of typing dense arrays of markers in regions of potential linkage , we have typed an additional nineteen microsatellite markers from this chr omosome 5 region (D5S623 - D5S428) in the same sibling pair families. The m ean additional information extracted per marker typed declined with increas ing map density, while inaccuracies in the mapping and the density of genot yping errors increased. Our empirical results suggest that, in linkage-base d experiments, there is a limit to the benefits that are gained from typing additional markers in the same families. Increasing map density up to the 2.5-5 cM level efficiently extracts valuable extra information; however, be yond this level efficiency declines while the confounding effects of mappin g and genotyping errors accumulate. We, therefore, recommend that extra mar kers typed in linkage studies be limited to this level of resolution. Mappi ng regions beyond this density should only be initiated when searching for linkage disequilibrium. Genet. Epidemiol. 17:51-63, 1999. (C) 1999 Wiley-Li ss, Inc.