Exploiting gene × gene interaction in linkage analysis

When two genes interact to cause a clinically important phenotype, it would seem reasonable to expect that we could leverage genotypic information at one of the loci in order to improve our ability to detect the other. We were therefore interested in extending the posterior probability of linkage (PPL), a class of linkage statistics we have been developing over the past decade, in order to explicitly allow for gene x gene interaction. In this report we utilize a new implementation of the PPL incorporating liability classes (LCs), which provide a direct parameterization of gene x gene interaction by allowing the penetrances at the locus being evaluated to depend upon measured genotypes at a known locus. With knowledge of the generating model for the simulated rheumatoid arthritis (RA) data, we selected two loci for examination: Locus A, which in interaction with the HLA-DR antigen locus affects risk of the dichotomous RA phenotype; and Locus E, which in interaction with DR affects quantitative levels of the anti-CCP phenotype. The data comprised nuclear families of two parents and an affected sib pair (ASP). Our results confirm theoretical work suggesting that gene x gene interactions CANNOT be leveraged to improve linkage detection for dichotomous traits based on affecteds-only data structures. However, incorporation of DR-based LCs did lead to appreciably higher quantitative trait PPLs. This suggests that gene x gene interactions could be effectively used in quantitative trait analyses even when families have been ascertained as ASPs for a related dichotomous trait.