A Family-Based Rare Haplotype Association Method for Quantitative Traits

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.