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Mixed linear model approach adapted for genome-wide association studies

Abstract

Mixed linear model (MLM) methods have proven useful in controlling for population structure and relatedness within genome-wide association studies. However, MLM-based methods can be computationally challenging for large datasets. We report a compression approach, called 'compressed MLM', that decreases the effective sample size of such datasets by clustering individuals into groups. We also present a complementary approach, 'population parameters previously determined' (P3D), that eliminates the need to re-compute variance components. We applied these two methods both independently and combined in selected genetic association datasets from human, dog and maize. The joint implementation of these two methods markedly reduced computing time and either maintained or improved statistical power. We used simulations to demonstrate the usefulness in controlling for substructure in genetic association datasets for a range of species and genetic architectures. We have made these methods available within an implementation of the software program TASSEL.

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Figure 1: The forms of MLM classified by the random effect size and types of kinship.
Figure 2: Quantile-quantile plots of type I error (false positive) rates of association tests using the compressed MLM under different compression levels.
Figure 3: The performance of the compressed MLM under different compression levels (horizontal axis).
Figure 4: The P values and statistical power of association tests obtained by using the one-step MLM with the full optimization (full OPT) for all unknown parameters compared to P3D on a maize phenotype simulated with different epistatic effects (E).

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Acknowledgements

This study was supported by the US National Science Foundation (NSF)–Plant Genome Program (DBI-0321467, 0703908 and 0820619), NSF–Plant Genome Comparative Sequencing Program (DBI-06638566), US National Institutes of Health (1R21AR055228-01A1), National Heart, Lung, and Blood Institute (U 01 HL72524, HL54776 and 5U01HL072524-06), US Department of Agriculture Research Service (53-K06–5-10 and 58–1950-9–001), USDA–Cooperative State Research, Education and Extension Service National Research Initiative (2006-35300-17155), Morris Animal Foundation (D04CA-135), WALTHAM Centre for Pet Nutrition, Cornell Advanced Technology in Biotechnology and the Collaborative Research Program in the Cornell Veterinary College. The authors would like to thank K. Zhao for providing the source code to compute kinship and L. Rigamer Lirette, A.L. Ingham and S. Myles for editing of the manuscript.

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Contributions

Z.Z. conceptualized the study, performed the data analyses and wrote the manuscript. E.E., M.A.G. and J.Y. participated in the data analyses and wrote the manuscript. P.J.B. implemented the two new methods in the TASSEL software package. C.L., H.K.T., D.K.A. and J.M.O. provided the human data and supervised its analyses. R.J.T. provided the dog data and supervised its analyses. E.S.B designed and supervised the project. All authors edited the manuscript.

Corresponding author

Correspondence to Zhiwu Zhang.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Note (PDF 1425 kb)

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Zhang, Z., Ersoz, E., Lai, CQ. et al. Mixed linear model approach adapted for genome-wide association studies. Nat Genet 42, 355–360 (2010). https://doi.org/10.1038/ng.546

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