Family-based association tests (FBATs) — case-parent-trios36, case-sibling37, designs using extended pedigrees38, and modified segregation analysis39 — are appealing because they avoid bias from population stratification, but are generally less powerful for testing main effects than case-control studies using unrelated controls. However, they can be more powerful for testing G×E interactions if relatives’ exposures are not too highly correlated37. Population stratification can bias G×E interactions only if the substructure is related to the gene and the environmental factor differentially—different ancestry-genotype associations in exposed and unexposed individuals—which seems unlikely. The case-parent trio design requires exposure information only on the cases (although it does require surviving parents for genotyping, making it more suitable for early-onset diseases) and entails a comparison of genetic relative risks between exposed and unexposed cases. The discordant sibship design requires exposure information on all cases and controls and uses standard conditional logistic regression tests of interaction. Twin studies40, segregation41, and linkage analysis42-44 can also be used for testing the existence of G×E with unknown genes or specific regions25.
