title: A unified mixed-effects model for rare-variant association in sequencing studies.
abstract: For rare-variant association analysis, due to extreme low frequencies of these variants, it is necessary to aggregate them by a prior set (e.g., genes and pathways) in order to achieve adequate power. In this paper, we consider hierarchical models to relate a set of rare variants to phenotype by modeling the effects of variants as a function of variant characteristics while allowing for variant-specific effect (heterogeneity). We derive a set of two score statistics, testing the group effect by variant characteristics and the heterogeneity effect. We make a novel modification to these score statistics so that they are independent under the null hypothesis and their asymptotic distributions can be derived. As a result, the computational burden is greatly reduced compared with permutation-based tests. Our approach provides a general testing framework for rare variants association, which includes many commonly used tests, such as the burden test [Li and Leal, 2008] and the sequence kernel association test [Wu et al., 2011], as special cases. Furthermore, in contrast to these tests, our proposed test has an added capacity to identify which components of variant characteristics and heterogeneity contribute to the association. Simulations under a wide range of scenarios show that the proposed test is valid, robust, and powerful. An application to the Dallas Heart Study illustrates that apart from identifying genes with significant associations, the new method also provides additional information regarding the source of the association. Such information may be useful for generating hypothesis in future studies.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Sun
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D017720:Molecular Epidemiology; D010641:Phenotype; D017422:Sequence Analysis, DNA; D012984:Software