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Am J Epidemiol. 2011 Nov 15;174(10):1183-9. doi: 10.1093/aje/kwr231. Epub 2011 Oct 20.

A sibling-augmented case-only approach for assessing multiplicative gene-environment interactions.

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National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.


Family-based designs protect analyses of genetic effects from bias that is due to population stratification. Investigators have assumed that this robustness extends to assessments of gene-environment interaction. Unfortunately, this assumption fails for the common scenario in which the genotyped variant is related to risk through linkage with a causative allele. Bias also plagues other methods of assessment of gene-environment interaction. When testing against multiplicative joint effects, the case-only design offers excellent power, but it is invalid if genotype and exposure are correlated in the population. The authors describe 4 mechanisms that produce genotype-exposure dependence: exposure-related genetic population stratification, effects of family history on behavior, genotype effects on exposure, and selective attrition. They propose a sibling-augmented case-only (SACO) design that protects against the former 2 mechanisms and is therefore valid for studying young-onset disease in which genotype does not influence exposure. A SACO design allows the ascertainment of genotype and exposure for cases and exposure for 1 or more unaffected siblings selected randomly. Conditional logistic regression permits assessment of exposure effects and gene-environment interactions. Via simulations, the authors compare the likelihood-based inference on interactions using the SACO design with that based on other designs. They also show that robust analyses of interactions using tetrads or disease-discordant sibling pairs are equivalent to analyses using the SACO design.

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