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Efficient Bayesian mixed-model analysis increases association power in large cohorts

Abstract

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.

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Figure 1: Computational performance of mixed-model association methods.
Figure 2: BOLT-LMM increases the power to detect associations in simulations.
Figure 3: BOLT-LMM increases the power to detect associations for WGHS phenotypes.

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Acknowledgements

We are grateful to M. Lipson, S. Simmons, A. Gusev, K. Galinsky, J. Yang, P. Visscher, Z. Zhu and D. Gudbjartsson for helpful discussions. This research was supported by US National Institutes of Health grant R01 HG006399 and US National Institutes of Health fellowship F32 HG007805. H.K.F. was supported by the Fannie and John Hertz Foundation. The WGHS is supported by HL043851 and grants HL080467 from the National Heart, Lung, and Blood Institute and grant CA047988 from the National Cancer Institute, by the Donald W. Reynolds Foundation and by the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen.

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Contributions

P.-R.L., N.P. and A.L.P. designed experiments. P.-R.L. performed experiments. P.-R.L., G.T., B.K.B.-S., B.J.V., H.K.F. and A.L.P. analyzed data. D.I.C. and P.M.R. provided data. All authors wrote the manuscript.

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Correspondence to Po-Ru Loh or Alkes L Price.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Tables 1–15 and Supplementary Note. (PDF 2591 kb)

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Loh, PR., Tucker, G., Bulik-Sullivan, B. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet 47, 284–290 (2015). https://doi.org/10.1038/ng.3190

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