Abstract

Genome-wide association studies (GWASs) are often confounded by population stratification and structure. Linear mixed models (LMMs) are a powerful class of methods for uncovering genetic effects, while controlling for such confounding. LMMs include random effects for a genetic similarity matrix, and they assume that a true genetic similarity matrix is known. However, uncertainty about the phylogenetic structure of a study population may degrade the quality of LMM results. This may happen in bacterial studies in which the number of samples or loci is small, or in studies with low-quality genotyping. In this study, we develop methods for linear mixed models in which the genetic similarity matrix is unknown and is derived from Markov chain Monte Carlo estimates of the phylogeny. We apply our model to a GWAS of multidrug resistance in tuberculosis, and illustrate our methods on simulated data.

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Published In

cover image Journal of Computational Biology
Journal of Computational Biology
Volume 30Issue Number 2February 2023
Pages: 189 - 203
PubMed: 36374242

History

Published online: 7 February 2023
Published in print: February 2023
Published ahead of print: 14 November 2022

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Authors

Affiliations

School of Statistics and Data Science, LPMC and KLMDASR, Nankai University, Tianjin, China.
Shufei Ge*
Institute of Mathematical Sciences, ShanghaiTech University, Shanghai, China.
Benjamin Sobkowiak
Department of Mathematics and Simon Fraser University, Burnaby, Canada.
Liangliang Wang
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, Canada.
Louis Grandjean
Department of Infectious Diseases, University College London, London, United Kingdom.
Caroline Colijn
Department of Mathematics and Simon Fraser University, Burnaby, Canada.
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, Canada.

Notes

*
These authors contributed equally to this study.
Address correspondence to: Dr. Lloyd T. Elliott, Department of Statistics and Actuarial Science, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada [email protected]

Authors' Contributions

S.W. and S.G. contributed to methodology, formal analysis, software, writing—original draft, and writing—review and editing. B.S. contributed to writing—original draft and writing—review and editing. L.G. contributed to data curation. L.W. contributed to writing—review and editing. C.C. contributed to conceptualization and writing—review and editing. L.T.E. contributed to conceptualization, methodology, writing—original draft and writing—review and editing.

Author Disclosure Statement

The authors declare they have no conflicting financial interests.

Funding Information

This research is supported by the National Natural Science Funds of China (Grant No. 12101333), the Natural Science Funds of Tianjin (Grant No. 21JCQNJC00050), the Shanghai Science and Technology Program (Grant No. 21010502500), the startup fund of ShanghaiTech University, and NSERC (Grant Nos. RGPIN/05484-2019, RGPIN/2019-06131, and DGECR/00118-2019). L.T.E. is supported by a Michael Smith Health Research BC Scholor Award.

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