Multipoint linkage analysis using affected relative pairs and partially informative markers

Linkage analysis is a method of identifying regions of the human genome har boring genes affecting the risk for a particular disease. It works by findi ng chromosomal segments inherited by affected relatives from a common ances tor (i.e., identical by descent or IBD) in excess of that expected by chanc e. Two complicating factors are that only a relatively small number of geno mic locations (marker loci) are examined and the number of distinct realiza tions (alleles) at each marker is not large. Hence, unambiguous determinati on of IBD is impossible for any genomic location without additional informa tion. Assuming data from a set of mapped, partially informative markers, we evaluate the effectiveness of a method that analyzes the array of markers on each chromosome jointly (multipoint methods) as a function of the inform ativeness and density of the markers. For the special case of pairs of half siblings whose parents are also typed, a combination of analysis and simul ation is used to obtain insight into the problem of setting thresholds to c ontrol the false-positive error rate. Approximations are given for the powe r, and guidelines are developed to help describe the trade-offs between mar ker density and informativeness.