BRASS: Permutation methods for binary traits in genetic association studies with structured samples

by Joelle Mbatchou, Mark Abney, Mary Sara McPeek In genetic association analysis of complex traits, permutation testing can be a valuable tool for assessing significance when the distribution of the test statistic is unknown or not well-approximated. This commonly arises, e.g, in tests of gene-set, pathway or genome-wide significance, or when the statistic is formed by machine learning or data adaptive methods. Existing applications include eQTL mapping, association testing with rare variants, inclusion of admixed individuals in genetic association analysis, and epistasis detection among many others. For genetic association testing in samples with population structure and/or relatedness, use of naive permutation can lead to inflated type 1 error. To address this in quantitative traits, the MVNpermute method was developed. However, for association mapping of a binary trait, the relationship between the mean and variance makes both naive permutation and the MVNpermute method invalid. We propose BRASS, a permutation method for binary traits, for use in association mapping in structured samples. In addition to modeling structure in the sample, BRASS allows for covariates, ascertainment and simultaneous testing of multiple markers, and it accommodates a wide range of test statistics. In simulation studies, we compare BRASS to other permutation and resampling-based methods in a range of scenarios that include population structure, familial relatedness, ascertainment and phenotype ...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research