One of the earliest non-traditional designs was the case-only (or “case-case”) design28, which can only be used for testing interactions, not main effects. This design relies on an assumption of gene-environment independence in the source population to avoid estimating this association among controls, thereby increasing power for the test of interaction. While this assumption would be reasonable for most exogenous exposures like air pollution, the case-only design will yield a biased estimate of ORG×E and an elevated type I error rate if the independence assumption is violated. For example, genes involved in behavioral traits such as addiction might be expected to produce a causal association between G and E (e.g. tobacco smoking29,30) in the general population. Other G-E associations could arise indirectly; for instance, between oral contraceptives and BRCA1 through the effect of the gene on family history — a sister of an affected case might choose to take oral contraceptives to lessen her risk of ovarian cancer31.
