Score Tests for Association between Traits and Haplotypes when Linkage Phase Is Ambiguous

Abstract

A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

“…28 However, as these SNPs studied here are tagging SNPs and most of them are not in linkage disequilibrium (LD) with each other, we did not find improved association by haplotype analysis in any genes (data not shown).…”

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men

“…45 The haplo.score function estimates haplotype frequencies via the expectation-maximization algorithm and performs statistical tests of association using score statistics for quantitative traits adjusting for the same covariates as included in the single SNP analyses. We performed haplotype analysis for each previously described block separately, and for the exonic SNPs between blocks 2 and 3.…”

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

“…Linkage disequilibrium was analysed by using the LDA software (Ding et al, 2003). 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).…”