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Widespread signatures of negative selection in the genetic architecture of human complex traits

Jian Zeng, Ronald de Vlaming, Yang Wu, Matthew R Robinson, Luke Lloyd-Jones, Loic Yengo, Chloe Yap, Angli Xue, Julia Sidorenko, Allan F McRae, Joseph E Powell, Grant W Montgomery, Andres Metspalu, Tonu Esko, Greg Gibson, Naomi R Wray, Peter M Visscher, Jian Yang
doi: https://doi.org/10.1101/145755
Jian Zeng
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Ronald de Vlaming
2Department of Complex Trait Genetics, VU University, Center for Neurogenomics and Cognitive Research, Amsterdam, 1081 HV, The Netherlands
3Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, 3062 PA, The Netherlands
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Yang Wu
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Matthew R Robinson
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
4Department of Computational Biology, University of Lausanne, 1011 Lausanne, Switzerland
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Luke Lloyd-Jones
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Loic Yengo
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Chloe Yap
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Angli Xue
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Julia Sidorenko
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Allan F McRae
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Joseph E Powell
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Grant W Montgomery
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Andres Metspalu
5Estonian Genome Center, University of Tartu, Tartu, Estonia
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Tonu Esko
5Estonian Genome Center, University of Tartu, Tartu, Estonia
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Greg Gibson
6School of Biology and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA
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Naomi R Wray
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
7Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Peter M Visscher
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
7Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Jian Yang
1Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
7Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Abstract

Estimation of the joint distribution of effect size and minor allele frequency (MAF) for genetic variants is important for understanding the genetic basis of complex trait variation and can be used to detect signature of natural selection. We develop a Bayesian mixed linear model that simultaneously estimates SNP-based heritability, polygenicity (i.e. the proportion of SNPs with nonzero effects) and the relationship between effect size and MAF for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752), and show that on average across 28 traits, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (p < 0.05/28 =1.8×10−3) signatures of natural selection for 23 out of 28 traits including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. We further apply the method to 27,869 gene expression traits (N = 1,748), and identify 30 genes that show significant (p < 2.3×10−6) evidence of natural selection. All the significant estimates of the relationship between effect size and MAF in either complex traits or gene expression traits are consistent with a model of negative selection, as confirmed by forward simulation. We conclude that natural selection acts pervasively on human complex traits shaping genetic variation in the form of negative selection.

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Posted June 03, 2017.
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Widespread signatures of negative selection in the genetic architecture of human complex traits
Jian Zeng, Ronald de Vlaming, Yang Wu, Matthew R Robinson, Luke Lloyd-Jones, Loic Yengo, Chloe Yap, Angli Xue, Julia Sidorenko, Allan F McRae, Joseph E Powell, Grant W Montgomery, Andres Metspalu, Tonu Esko, Greg Gibson, Naomi R Wray, Peter M Visscher, Jian Yang
bioRxiv 145755; doi: https://doi.org/10.1101/145755
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Widespread signatures of negative selection in the genetic architecture of human complex traits
Jian Zeng, Ronald de Vlaming, Yang Wu, Matthew R Robinson, Luke Lloyd-Jones, Loic Yengo, Chloe Yap, Angli Xue, Julia Sidorenko, Allan F McRae, Joseph E Powell, Grant W Montgomery, Andres Metspalu, Tonu Esko, Greg Gibson, Naomi R Wray, Peter M Visscher, Jian Yang
bioRxiv 145755; doi: https://doi.org/10.1101/145755

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