Partitioned association-linkage test: distinguishing "necessary" from "susceptibility" loci

Marker allele-disease association and linkage between a disease locus and a marker locus are two different phenomena. Linkage without evidence of association and association without evidence of linkage are possible observations. Linkage analysis uses marker loci and the phenomenon of recombination to look for disease-related loci which are presumably major contributors to disease expression ("necessary" loci). However, the phenomenon of association is more complex. One explanation for the existence of an association is that there is a "necessary" locus in linkage disequilibrium with a marker locus. Another explanation is that the marker locus itself (or a closely linked locus in linkage disequilibrium with the marker) is a "susceptibility" locus, which increases the probability of contracting the disease but is not necessary for disease expression. Although there are other possible explanations for the existence of an association, these two can lead to different results when family data from a disease showing association are analyzed for linkage between the associated marker and the disease. If the linkage disequilibrium hypothesis is correct, there will be evidence for linkage. If the susceptibility locus hypothesis is correct, there may be strong evidence against linkage. In this work, we explore a method that could indicate whether an association is due to a susceptibility locus or a necessary locus. We show that, by dividing families based on the presence or absence of the associated marker allele in a randomly chosen affected sib, calculating lod scores, and then calculating a heterogeneity statistic, we could distinguish whether linkage data came from a susceptibility locus or a necessary locus.