Does simultaneous consideration of multiple regions improve disease gene localization?

Improvement in localization of disease susceptibility genes by simultaneous consideration of multiple interacting loci was assessed using the Genetic Analysis Workshop 12 simulated data. Evidence of linkage at primary loci was used to weight families for analyses at secondary loci. To identify regions linked to disease susceptibility genes, parametric and allele-sharing genome scans were performed in the extended pedigrees and nuclear families, respectively. The position of the peak allele-sharing lod was used as the estimate of a disease gene location. In weighted analyses, the positions where the greatest lod increases occurred were taken as alternative estimates of the gene locations. Variability of the location estimates of disease genes given by the unweighted and weighted analyses was compared. Similar analyses were carried out using true disease loci to determine weights. Weighted analyses did not in general improve the localization of disease genes in this data set, even with a large sample of 1,928 nuclear families, due to the features of the underlying additive liability threshold model.