Robust multipoint linkage analysis: an extension of the Haseman-Elston method.

The use of multiple markers, rather than a single marker, can increase the likelihood of detecting linkage to a locus underlying a quantitative trait. In this paper, the Haseman-Elston sibpair method is extended to include information from multiple markers. The result is a linear regression of the squared pair trait difference on the jointly estimated proportions of genes shared identical by descent at the two closest flanking marker loci. The results strengthen the theoretical motivation for the interval mapping technique proposed by Fulker and Cardon [1994: Am J Hum Genet 54:1092-1103] and extend the method to include information from multiple markers, account for a trait dominance component, and examine the region just outside that defined by the markers. Simulations show that modest increases in power and substantial decreases in bias of parameter estimates are obtained when identity-by-descent probabilities are jointly estimated. The regression relationship is also developed for other types of relative pairs.