Efficient Bayesian mixed-model analysis increases association power in large cohorts
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Open Access
- 2 February 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 47 (3), 284-290
- https://doi.org/10.1038/ng.3190
Abstract
Alkes Price, Po-Ru Loh and colleagues report the BOLT-LMM method for mixed-model association. They apply their method to 9 quantitative traits in 23,294 samples and demonstrate that it provides improvements in computational efficiency as well as gains in power that increase with the size of the cohort, making it useful for the analysis of large cohorts. Linear mixed models are a powerful statistical tool for identifying genetic associations and avoiding confounding. However, existing methods are computationally intractable in large cohorts and may not optimize power. All existing methods require time cost O(MN2) (where N is the number of samples and M is the number of SNPs) and implicitly assume an infinitesimal genetic architecture in which effect sizes are normally distributed, which can limit power. Here we present a far more efficient mixed-model association method, BOLT-LMM, which requires only a small number of O(MN) time iterations and increases power by modeling more realistic, non-infinitesimal genetic architectures via a Bayesian mixture prior on marker effect sizes. We applied BOLT-LMM to 9 quantitative traits in 23,294 samples from the Women's Genome Health Study (WGHS) and observed significant increases in power, consistent with simulations. Theory and simulations show that the boost in power increases with cohort size, making BOLT-LMM appealing for genome-wide association studies in large cohorts.Keywords
This publication has 48 references indexed in Scilit:
- MASTOR: Mixed-Model Association Mapping of Quantitative Traits in Samples with Related IndividualsAmerican Journal of Human Genetics, 2013
- A mixed-model approach for genome-wide association studies of correlated traits in structured populationsNature Genetics, 2012
- An efficient multi-locus mixed-model approach for genome-wide association studies in structured populationsNature Genetics, 2012
- Genome-wide efficient mixed-model analysis for association studiesNature Genetics, 2012
- Bayesian inference analyses of the polygenic architecture of rheumatoid arthritisNature Genetics, 2012
- Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosisNature, 2011
- Genomic inflation factors under polygenic inheritanceEuropean Journal of Human Genetics, 2011
- A Generalized Family-Based Association Test for Dichotomous TraitsAmerican Journal of Human Genetics, 2009
- Principal components analysis corrects for stratification in genome-wide association studiesNature Genetics, 2006
- A unified mixed-model method for association mapping that accounts for multiple levels of relatednessNature Genetics, 2005