Linkage-disequilibrium mapping of disease genes by reconstruction of ancestral haplotypes in founder populations

Linkage disequilibrium (LD) mapping may be a powerful means for genome screening to identify susceptibility loci for common diseases. Anew statistical approach for detection of LD around a disease gene is presented here. This method compares the distribution of haplotypes in affected individuals versus that expected for individuals descended from a common ancestor who carried a mutation of the disease gene. Simulations demonstrate that this method, which we term "ancestral haplotype reconstruction" (AHR), should be powerful for genome screening of phenotypes characterized by a high degree of etiologic heterogeneity, even with currently available marker maps; AHR is best suited to application in isolated populations where affected individuals are relatively recently descended (<similar to 25 generations) from a common disease mutation-bearing founder.