A joint test of linkage and genexenvironment interaction, with affected sib pairs

In the presence of genexenvironment (GxE) interaction, the expected proport ion of alleles shared identical by descent at a linked marker locus by a pa ir 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 l inkage to test for differential identical-by-descent (IBD) sharing across s ib-exposure profiles. The method can be viewed as a test for linkage in the presence of GxE interaction, or as a test for GxE interaction in the prese nce of linkage. Applied to the simulated GAW11 data, our method successfull y localized disease locus C and its interactive relationship with environme ntal factor E1. At the 5% significance level, use of our method led to incr eased power to detect linkage (56%) to this disease locus compared to use o f the standard mean test (32%); at the 0.001 significance level, the corres ponding power estimates were 20% and 4%, respectively. For a gene that inte racts with an environmental factor, we conclude that use of the environment al factor in linkage analysis can improve detection rates while also provid ing information about underlying mechanisms. ((C)) 1999 Wiley-Liss, Inc.