Estimation and Tests of Haplotype-Environment Interaction when Linkage Phase Is Ambiguous

TLDR

Linkage analysis and single‑marker tests are limited for studying gene–environment interactions, and although haplotypes may be more suitable, they are often unobservable in standard genotyping, leaving researchers with only unphased marker phenotypes. The study introduces a method to estimate and test haplotype–environment interactions when linkage phase is ambiguous. The method extends Schaid et al.’s framework to generalized linear models and is evaluated via simulations. Applying the method to the Childhood Asthma Management Program data revealed a haplotype–smoking interaction.

Abstract

In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al. [2002] and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.