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Nat Genet. 2018 May;50(5):746-753. doi: 10.1038/s41588-018-0101-4. Epub 2018 Apr 16.

Signatures of negative selection in the genetic architecture of human complex traits.

Author information

1
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
2
School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
3
Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, The Netherlands.
4
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
5
Estonian Genome Center, University of Tartu, Tartu, Estonia.
6
School of Biological Sciences and Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA.
7
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
8
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. jian.yang@uq.edu.au.
9
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia. jian.yang@uq.edu.au.

Abstract

We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency 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 (Nā€‰=ā€‰126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (Pā€‰<ā€‰0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.

PMID:
29662166
DOI:
10.1038/s41588-018-0101-4

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