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LiMMBo: a simple, scalable approach for linear mixed models in high-dimensional genetic association studies

View ORCID ProfileHannah Verena Meyer, Francesco Paolo Casale, View ORCID ProfileOliver Stegle, View ORCID ProfileEwan Birney
doi: https://doi.org/10.1101/255497
Hannah Verena Meyer
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
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Francesco Paolo Casale
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
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Oliver Stegle
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
2European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
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Ewan Birney
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom
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Abstract

Genome-wide association studies have helped to shed light on the genetic architecture of complex traits and diseases. Deep phenotyping of population cohorts is increasingly applied, where multi-to high-dimensional phenotypes are recorded in the individuals. Whilst these rich datasets provide important opportunities to analyse complex trait structures and pleiotropic effects at a genome-wide scale, existing statistical methods for joint genetic analyses are hampered by computational limitations posed by high-dimensional phenotypes. Consequently, such multivariate analyses are currently limited to a moderate number of traits. Here, we introduce a method that combines linear mixed models with bootstrapping (LiMMBo) to enable computationally efficient joint genetic analysis of high-dimensional phenotypes. Our method builds on linear mixed models, thereby providing robust control for population structure and other confounding factors, and the model scales to larger datasets with up to hundreds of phenotypes. We first validate LiMMBo using simulations, demonstrating consistent covariance estimates at greatly reduced computational cost compared to existing methods. We also find LiMMBo yields consistent power advantages compared to univariate modelling strategies, where the advantages of multivariate mapping increases substantially with the phenotype dimensionality. Finally, we applied LiMMBo to 41 yeast growth traits to map their genetic determinants, finding previously known and novel pleiotropic relationships in this high-dimensional phenotype space. LiMMBo is accessible as open source software (https://github.com/HannahVMeyer/limmbo).

Author summary In multi-trait genetic association studies one is interested in detecting genetic variants that are associated with one or multiple traits. Genetic variants that influence two or more traits are referred to as pleiotropic. Multivariate linear mixed models have been successfully applied to detect pleiotropic effects, by jointly modelling association signals across traits. However, these models are currently limited to a moderate number of phenotypes as the number of model parameters grows steeply with the number of phenotypes, raising a computational burden. We developed LiMMBo, a new approach for the joint analysis of high-dimensional phenotypes. Our method reduces the number of effective model parameters by introducing an intermediate subsampling step. We validate this strategy using simulations, where we apply LiMMBo for the genetic analysis of hundreds of phenotypes, detecting pleiotropic effects for a wide range of simulated genetic architectures. Finally, to illustrate LiMMBo in practice, we apply the model to a study of growth traits in yeast, where we identify pleiotropic effects for traits with formerly known genetic effects as well as revealing previously unconnected traits.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 30, 2018.
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LiMMBo: a simple, scalable approach for linear mixed models in high-dimensional genetic association studies
Hannah Verena Meyer, Francesco Paolo Casale, Oliver Stegle, Ewan Birney
bioRxiv 255497; doi: https://doi.org/10.1101/255497
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LiMMBo: a simple, scalable approach for linear mixed models in high-dimensional genetic association studies
Hannah Verena Meyer, Francesco Paolo Casale, Oliver Stegle, Ewan Birney
bioRxiv 255497; doi: https://doi.org/10.1101/255497

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