Testing Association of Statistically Inferred Haplotypes with Discrete and Continuous Traits in Samples of Unrelated Individuals

Abstract

There have been increasing efforts to relate drug efficacy and disease predisposition with genetic polymorphisms. We present statistical tests for association of haplotype frequencies with discrete and continuous traits in samples of unrelated individuals. Haplotype frequencies are estimated through the expectation-maximization algorithm, and each individual in the sample is expanded into all possible haplotype configurations with corresponding probabilities, conditional on their genotype. A regression-based approach is then used to relate inferred haplotype probabilities to the response. The relationship of this technique to commonly used approaches developed for case-control data is discussed. We confirm the proper size of the test under H₀ and find an increase in power under the alternative by comparing test results using inferred haplotypes with single-marker tests using simulated data. More importantly, analysis of real data comprised of a dense map of single nucleotide polymorphisms spaced along a 12-cM chromosomal region allows us to confirm the utility of the haplotype approach as well as the validity and usefulness of the proposed statistical technique. The method appears to be successful in relating data from multiple, correlated markers to response.

Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study

“…24 In addition to the adjustment for multiple testing, we also conducted haplotype association analyses using trend regression to avoid multiple testing and to increase statistical power. 27 The haplotype association analyses were restricted in haplotypes of two polymorphisms (G-6A and M235T), because of a high linkage disequilibrium between G-6A and T174M (r ¼ 0.97), and T174M associated with cardiovascular phenotype most likely through the partial disequilibrium with alleles at codon 235. 4 This two-polymorphism haplotype association analysis further increased the statistical power.…”

Impact of complex genetic variation in COMT on human brain function

“…We used the haplotype trend regression (HTR) approach 27 to test for association between BOLD signal response and estimated haplotype frequencies. Since we examined the association with an intermediate biological phenotype, we assumed codominance, allowing us to model and analyze the effect of each haplotype separately.…”

“…For single quantitative traits, both score-based 26 and regression-based 4,27 approaches have been proposed, but the application of these methods to high-dimensional phenotype data sets such as that derived from neuroimaging is not straightforward. Here, we describe a novel approach to this problem, which operates by a two-step method: first, we adapt a regression method 27 to estimate the effects of ambiguous haplotypes on imaging data. In a second step, we apply Gaussian Random fields (GRF) theory 28 to effect stringent multiple comparison control over the multiple datapoints studied in neuroimaging.…”

COX2 genetic variation, NSAIDs, and advanced prostate cancer risk

“…Haplotype dosage (i.e. an estimate of the number of copies of haplotype h) for each individual and each haplotype, h, was computed using that individual's genotype data and haplotype frequency estimates were obtained from the E-M algorithm (Zaykin et al, 2002). Odds ratios and 95% CIs were then estimated by unconditional logistic regression for the association between COX2 haplotypes and prostate cancer risk.…”