Method to detect genotype-environment interactions for quantitative trait loci in association studies.

Khoury et al. (Am J Hum Genet 1988;42:89-95 and Am J Epidemiol 1993;137:1241-50) presented an epidemiologic approach to examine genotype-environment interaction in situations where the disease is either present or absent. In this article, the author extends the approach of Khoury et al. to quantitative outcome variables. This extension is relevant for diseases that are extremes on a continuum or when continuous risk factors are studied. To account for a possible admixture of subgroups in the sample, tests for genotype-environment interaction are discussed for designs with parents as controls as well as without parents as controls. Assuming two environmental conditions, the author demonstrates how the power of these tests can be calculated and used to estimate the sample sizes needed to detect genotype-environment interaction in a variety of conditions. In addition, he analyzes simulated data to demonstrate the detection of different mechanisms of genotype-environment interaction and to study the effectiveness of this approach to identify the correct mechanism. Finally, extensions to multiple environmental conditions and designs with multiple subjects per family are discussed.