Gene-Environment Interaction and Affected Sib Pair Linkage Analysis

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Abstract
Objectives: Gene-environment (G×E) interaction influences risk for many complex disease traits. However, genome screens using affected sib pair linkage techniques are typically conducted without regard for G×E interaction. We propose a simple extension of the commonly used mean test and evaluate its power for several forms of G×E interaction. Methods: We compute expected IBD sharing by sibling exposure profile, that is by whether two sibs are exposed (EE), unexposed (UU), or are discordant for exposure (EU). We describe a simple extension of the mean test, the ‘mean-interaction’ test that utilizes heterogeneity in IBD sharing across EE, EU, and UU sib pairs in a test for linkage. Results: The mean-interaction test provides greater power than the mean test for detecting linkage in the presence of moderate or strong G×E interaction, typically when the interaction relative risk (Rge) exceeds 3 or is less than 1/3. In the presence of strong interaction (Rge = 10), the required number of affected sib pairs to achieve 80% power for detecting linkage is approximately 30% higher when the environmental factor is ignored in the mean test, than when it is utilized in the mean-interaction test. Conclusion: Linkage methods that incorporate environmental data and allow for interaction can lead to increased power for localizing a disease gene involved in a G×E interaction.