Transmission/disequilibrium tests for extended marker haplotypes

A generalization of the transmission/disequilibrium test to detect association between polymorphic markers and discrete or quantitative traits is discussed, with particular emphasis on marker haplotypes formed by several adjacent loci. Furthermore, strategies for testing haplotype association, using methods from spatial statistics, are developed. This approach compares the "similarity" of transmitted and untransmitted haplotypes, with the aim of determining the regions where there is greater similarity within the transmitted set. This arises from the fact that, although the original haplotypes carrying the mutation will be broken down by recombination, there may be a subset of markers near the mutation that are common to many of the recombinant haplotypes. Thus, by examination of each marker in turn and by measurement of the average size of the region shared identically by state in the transmitted and untransmitted haplotypes, it may be possible to detect regions of linkage disequilibrium that encompass the susceptibility gene.