A joint test of linkage and gene x environment interaction, with affected sib pairs

In the presence of gene x environment (G x E) interaction, the expected proportion of alleles shared identical by descent at a linked marker locus by a pair of affected sibs depends on the exposure profile of the two sibs, i.e., whether both are exposed to E, only one is exposed, or neither are exposed. In this paper, we propose an extension of the commonly used mean test of linkage to test for differential identical-by-descent (IBD) sharing across sib-exposure profiles. The method can be viewed as a test for linkage in the presence of G x E interaction, or as a test for G x E interaction in the presence of linkage. Applied to the simulated GAW11 data, our method successfully localized disease locus C and its interactive relationship with environmental factor E1. At the 5% significance level, use of our method led to increased power to detect linkage (56%) to this disease locus compared to use of the standard mean test (32%); at the 0.001 significance level, the corresponding power estimates were 20% and 4%, respectively. For a gene that interacts with an environmental factor, we conclude that use of the environmental factor in linkage analysis can improve detection rates while also providing information about underlying mechanisms.