A POWERFUL LIKELIHOOD METHOD FOR THE ANALYSIS OF LINKAGE DISEQUILIBRIUM BETWEEN TRAIT LOCI AND ONE OR MORE POLYMORPHIC MARKER LOCI

Historically, most methods for detecting linkage disequilibrium were d esigned for use with diallelic marker loci, for which the analysis is straightforward. With the advent of polymorphic markers with many alle les, the normal approach to their analysis has been either to extend t he methodology for two-allele systems (leading to an increase in df an d to a corresponding loss of power) or to select the allele believed t o be associated and then collapse the other alleles, reducing, in a bi ased way, the locus to a diallelic system. I propose a likelihood-base d approach to testing for linkage disequilibrium, an approach that bec omes more conservative as the number of alleles increases, and as the number of markers considered jointly increases in a multipoint test fo r linkage disequilibrium, while maintaining high power. Properties of this method for detecting associations and fine mapping the location o f disease traits are investigated. It is found to be, in general, more powerful than conventional methods, and it provides a tractable frame work for the fine mapping of new disease loci. Application to the cyst ic fibrosis data of Kerem et al. is included to illustrate the method.