Testing Haplotype-Environment Interactions Using Case-Parent Triads

Objective: Joint analysis of multiple SNP markers can be informative, but studying joint effects of haplotypes and environmental exposures is challenging. Population structure can involve both genes and exposures and a case-control study is susceptible to bias from either source of stratification. We propose a procedure that uses case-parent triad data and, though not fully robust, resists bias from population structure. Methods: Our procedure assumes that haplotypes under study have no influence on propensity to exposure. Then, under a no-interaction null hypothesis (multiplicative scale), transmission of a causative haplotype from parents to affected offspring might show distortion from Mendelian proportions but should be independent of exposure. We used this insight to develop a permutation test of no haplotype-by-exposure interaction. Results: Simulations showed that our proposed test respects the nominal Type I error rate and provides good power under a variety of scenarios. We illustrate by examining whether SNP variants in GSTP1 modify the association between maternal smoking and oral clefting. Conclusion: Our procedure offers desirable features: no need for haplotype estimation, validity under unspecified genetic main effects, tolerance to Hardy-Weinberg disequilibrium, ability to handle missing genotypes and a relatively large number of SNPs. Simulations suggest resistance to bias due to exposure-related population stratification.