title: On the use of allelic transmission rates for assessing gene-by-environment interaction in case-parent trios.
abstract: Allelic transmission rates from parents to cases are frequently stratified by an environmental risk factor E and compared, with heterogeneity interpreted as gene-environment interaction or GxE. Though generally invalid, such analyses continue to appear. We revisit why heterogeneity is not equivalent to GxE in a range of settings not considered previously. The objective is a fuller understanding of the bias in transmission rates and what is driving it. Extending previously published findings, we derive parental mating-type probabilities in cases and use them to obtain transmission rates, which we then compare to GxE. Through simulation, we investigate the practical implications of the bias for a transmission-based test of GxE. We find that general population characteristics distort the picture of GxE obtained from transmission rates: the stratum-specific mating-type probabilities under G - E dependence and the allele frequency under independence. Furthermore, the transmission-based test has inflated error rates relative to a likelihood-based test. Our investigation provides further insight into how and why transmission-based tests and descriptive summaries can mislead about GxE. For exploring GxE, we suggest graphical displays of the transmission rates within parental mating types, as they are robust to population stratification and the penetrance model.
authors.affiliation: Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada. shin@sfu.ca
authors.forename: Ji-Hyung
authors.initials: JH
authors.lastname: Shin
authors.forename: Brad
authors.initials: B
authors.lastname: McNeney
authors.forename: Jinko
authors.initials: J
authors.lastname: Graham
mesh_terms: D000483:Alleles; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010290:Parents; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide