HLA-associated diseases: a new method for performing linkage analysis with other markers than HLA.

It has been shown that genetic factors within the HLA region are involved in the etiology of several diseases. For some of these, the existence of another genetic factor has been suggested, although not proven. A possible way to give evidence for another locus (G) is to show that the disease and an unlinked HLA-marker locus (M) do not segregate independently. The usual lod-score method, which assumes monogenic inheritance, is inappropriate for this test. We propose a correction of this method for performing a linkage analysis between the G and M loci, taking into account the role of HLA. A very simple way of using the HLA information is by modifying, for each individual of a pedigree, the penetrance values at the G locus according to the number of HLA haplotypes shared with the index case. These penetrance values are inferred from the observed IBD (identity-by-descent) distribution of HLA haplotypes in a sample of affected sib-pairs. The advantage of using this empirical distribution is that it is not based on any assumptions concerning the mode of inheritance at the HLA-linked locus. This correction method was established using a two-locus model with restrictive assumptions. Its value is discussed for various sets of parameters in more general and realistic two-locus models using simulations.