AbstractLinkage analysis was performed on the GAW11 Problem 2 data set using stratification to explore the effects of the environmental risk factors and the differences between mild and severe phenotypes. Analysis of the four study populations stratified by the two risk factors identified regions on chromosomes 3 and 5 with significant evidence for linkage. Other loci were sought by removing families consistent with linkage to the chromosome 3 locus. Our studies identified a locus on chromosome 3 (markers 43–46) associated with the mild phenotype in the presence of risk factor 1 and with the severe phenotype independent of risk factor 1. This suggests that distinct allelic variants at the chromosome 3 locus may cause different forms of disease. The locus identified on chromosome 5 (markers 36–39) was linked to the severe phenotype, but exposure to factor 1 or 2 may have a protective effect. The regions on chromosomes 3 and 5 appeared to have independent roles in disease etiology. Evidence for two loci on chromosome 1 linked to the mild form was found. The methods successfully identified linkages and interaction consistent with the generating model.