Recent literature has highlighted the advantages of haplotype association methods for detecting rare variants associated with common diseases. As several new haplotype association methods have been proposed in the past few years, a comparison of new and standard methods is important and timely for guidance to the practitioners. We consider nine methods-Haplo.score, Haplo.glm, Hapassoc, Bayesian hierarchical Generalized Linear Model (BhGLM), Logistic Bayesian LASSO (LBL), regularized GLM (rGLM), Haplotype Kernel Association Test, wei-SIMc-matching and Weighted Haplotype and Imputation-based Tests. These can be divided into two types-individual haplotype-specific tests and global tests depending on whether there is just one overall test for a haplotype region (global) or there is an individual test for each haplotype in the region. Haplo.score is the only method that tests for both; Haplo.glm, Hapassoc, BhGLM and LBL are individual haplotype-specific, while the rest are global tests. For comparison, we also apply a popular collapsing method-Sequence Kernel Association Test (SKAT) and its two variants-SKAT-O (Optimal) and SKAT-C (Combined). We carry out an extensive comparison on our simulated data sets as well as on the Genetic Analysis Workshop (GAW) 18 simulated data. Further, we apply the methods to GAW18 real hypertension data and Dallas Heart Study sequence data. We find that LBL, Haplo.score (global test) and rGLM perform well over the scenarios considered here. Also, haplotype methods are more powerful (albeit more computationally intensive) than SKAT and its variants in scenarios where multiple causal variants act interactively to produce haplotype effects.

Several variants have been implicated earlier on ULK4 and MAP4 genes on chromosome 3 to be associated with hypertension. As a natural follow-up step, we explore association of haplotypes in those genes. We consider the Genetic Analysis Workshop 19 real data on unrelated individuals and analyze haplotype blocks of 5 single-nucleotide polymorphisms through a sliding window approach. We apply 4 haplotype association methods—haplo.score, haplo.glm, hapassoc, and logistic Bayesian LASSO (LBL)—and for comparison, sequence kernel association test (SKAT) and its variants. We find several rare haplotype blocks to be associated. To get an idea about the false-positive proportions, we also analyzed the data after permuting the case-control status of individuals. We found that LBL, unlike the other methods, maintains low false-positive rates in presence of rare haplotypes. Thus, we conclude that the haplotypes found to be associated by LBL are more likely to be true positive. SKAT and its variants did not find significance on either gene.

Background: The variants identified in genome-wide association studies account for only a small fraction of disease heritability. A key to this “missing heritability” is believed to be rare variants. Specifically, we focus on rare haplotype variant (rHTV). The existing methods for detecting rHTV are mostly population-based, and as such, are susceptible to population stratification and admixture, leading to an inflated false-positive rate. Family-based methods are more robust in this respect. Methods: We propose a method for detecting rHTVs associated with quantitative traits called family-based quantitative Bayesian LASSO (famQBL). FamQBL can analyze any type of pedigree and is based on a mixed model framework. We regularize the haplotype effects using Bayesian LASSO and estimate the posterior distributions using Markov chain Monte Carlo methods. Results: We conduct simulation studies, including analyses of Genetic Analysis Workshop 18 simulated data, to study the properties of famQBL and compare with a standard family-based haplotype association test implemented in FBAT (family-based association test) software. We find famQBL to be more powerful than FBAT with well-controlled false-positive rates. We also apply famQBL to the Framingham Heart Study data and detect an rHTV associated with diastolic blood pressure. Conclusion: FamQBL can help uncover rHTVs associated with quantitative traits.