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

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.

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

“…There were no statistically significant SNPs results associated with an increased risk of INH-induced hepatotoxicity in CES2 or CES4 (data not shown). Table 4 summarizes the results of association tests of haplotypes predicted using the Haplo.stats package 38 in the Genetic variation in CES genes and INH hepatotoxicity S Yamada et al high LD region of CES1, including SNP10, SNP11 and SNP13-21. We compared haplotype frequencies in all cases vs all controls, with adjustment for age and sex.…”

“…Adjustment was made for multiple testing by computing the false discovery rate. 37 The Haplo.stats package 38 was used to test associations between statistically inferred haplotypes and hepatotoxicity, and to calculate adjusted odds ratios (ORs) and 95% confidence intervals for each haplotype. Haplotypes with frequencies 45% were tested.…”

A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer

“…Haplo.score approach (Schaid et al, 2002) was used to test the association of statistically inferred haplotypes with lung cancer. As haplo.score does not provide the magnitude of the effect of each haplotype, haplo.glm was performed to calculate adjusted ORs and 95% confidence intervals (CIs) for each haplotype (Lake et al, 2003). Both haplo.score and haplo.glm were implemented in the haplo.-stats software developed by using the R language.…”

Genetic variation in five genes important in telomere biology and risk for breast cancer

“…Age was considered as a continuous variable in tests for genotype -age interactions. Haplotypes were constructed for cases and controls using PHASE v2.1 (Stephens et al, 2001;Stephens and Donnelly, 2003) and HaploStats (Lake et al, 2003). The global case -control permutation test was performed using PHASE v2.1 (Stephens et al, 2001;Stephens and Donnelly, 2003).…”

“…The global case -control permutation test was performed using PHASE v2.1 (Stephens et al, 2001;Stephens and Donnelly, 2003). HaploStats (Lake et al, 2003) was used also to determine the global score P-value, haplotype frequencies, ORs and 95% CIs.…”