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.


CONCLUSIONS
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.
Shi
Min
M
Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, NC 27709, USA.
Umbach
David M
DM
Weinberg
Clarice R
CR
D006239:Haplotypes; D006801:Humans; D008962:Models, Theoretical; D020641:Polymorphism, Single Nucleotide