A generalized estimating equations approach to linkage analysis in sibships in relation to multiple markers and exposure factors.

We describe a multiple regression approach to nonparametric linkage analysis in sibships incorporating multiple genetic loci, environmental covariates, and interactions. The covariance in trait residuals between sib pairs is treated as the dependent variable, regressed upon identical-by-descent sharing probabilities and interaction effects, using generalized estimating equations to allow for the correlations among multiple sib pairs within a sibship. Individual covariates can also be introduced in the model for the trait means. An application to the GAW11 simulated data revealed linkage with each of the four simulated loci, as well as gene x environment interactions of E1 with loci C and D and gene x gene interactions among the cluster of loci A, B, and D.