Impact of preadjusting a quantitative phenotype prior to sib-pair linkage analysis when gene(x)environment interaction exists

The investigation of potential genex environment (GxE) interactions is an i mportant facet in the study of complex diseases. When GxE interaction exist s, linkage analyses of the interacting gene must treat the environmental fa ctor appropriately. Specifically, the common approach of regressing out an environmental factor prior to linkage analysis may be inappropriate if that factor has an interaction with the gene. This is explored here in the Gene tic Analysis Workshop 12 simulated data set using the GxE interaction betwe en major gene four (MG4) and environmental factor two (E2). The analysis sh ows that preadjusting the quantitative trait three (Q3) phenotype for the m ain effects of several environmental variables, including one (E2) that int eracts with MG4, affects the results of a Haseman-Elston linkage analysis. In particular, the agreement in detecting linkage between preadjusting vers us not preadjusting was only 78% and 66% using alpha levels of 0.05 and 0.1 0, respectively. For both approaches, incorporating an interaction term in the regression models enabled linkage to be detected where the evidence was either minimal or not present in an identical-by-descent main effects-only model. Furthermore, preadjustment for E2 did not appear to account for the major discrepancies between the approaches. (C) 2001 Wiley Liss, Inc.