Using Cases and Parents to Study Multiplicative Gene-by-Environment Interaction

摘要

With case-parent triads, one can estimate genotype relative risks bymeasuring the apparent overtransmission ofnsusceptibility genotypes from parents to affected offspring. Results obtained using such designs, properly ana-nlyzed, resist both bias due to population structure and bias due to self-selection. Most diseases are not purelyngenetic, and environmental cofactors can also be important. In this paper, the authors describe how a polytomousnlogistic regression method previously developed for studying genetic effects on a quantitative trait can be used withncase-parent data to study multiplicative gene-by-environment interaction. The idea is that if the joint effect ofnexposure and genotype on risk is submultiplicative or supermultiplicative, then, conditional on the parental geno-ntypes, inheritance of a susceptibility genotype by affected offspring will appear to have been influenced by thenoffspring’s exposure level. The authors’ approach tolerates exposure-complicated genetic population structure,nand simulations suggest power and Type I error rates comparable to those of competitors. With this approach, onencan estimate the usual interaction parameters under a much less stringent assumption than gene-environmentnindependence in the source population. Incompletely genotyped triads can contribute through an expectation-nmaximization algorithm. To illustrate, the authors consider polymorphisms in detoxification pathway genes andnmaternal smoking in relation to the birth defect oral cleft.