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.
© 2010 S. Karger AG, Basel
- Haplotype-environment interaction
- Gene-environment interaction
- Case-parent triad
- Permutation test
- Non-parametreic test
- Population stratification
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Dr. Clarice R. Weinberg
Biostatistics Branch, Mail Drop: A3-03 101/A315
National Institute of Environmental Health Sciences
Research Triangle Park, NC 27709 (USA)
Tel. +1 919 541 4927, Fax +1 919 541 4311, E-Mail firstname.lastname@example.org
Received: August 3, 2009
Accepted after revision: January 31, 2010
Published online: April 23, 2010
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 2, Number of References : 19
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 70, No. 1, Year 2010 (Cover Date: June 2010)
Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
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