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

Jian Zeng; Ronald De Vlaming; Yang Wu; Matthew R. Robinson; Luke R. Lloyd-Jones; Loic Yengo; Chloe X. 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:10.1038/s41588-018-0101-4

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

Jian Zeng, Ronald De Vlaming, Yang Wu, Matthew R. Robinson, Luke R. Lloyd-Jones, Loic Yengo, Chloe X. 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^*

^*Corresponding author for this work

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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 (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 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.

Original language	English
Pages (from-to)	746-753
Number of pages	8
Journal	Nature Genetics
Volume	50
Issue number	5
Early online date	16 Apr 2018
DOIs	https://doi.org/10.1038/s41588-018-0101-4
Publication status	Published - May 2018

Funding

This research was supported by the Australian Research Council (DP160101343, DP160101056, DP160103860, and DP160102400), the Australian National Health and Medical Research Council (1107258, 1078901, 1078037, 1083656, 1078399, 1046880, and 1113400), the US National Institutes of Health (MH100141, GM099568, ES025052, and AG042568), and the Sylvia & Charles Viertel Charitable Foundation (Senior Medical Research Fellowship). R.d.V. acknowledges funding from an ERC consolidator grant (647648 EdGe, awarded to Philipp Koellinger). We thank The University of Queensland’s Research Computing Centre (RCC) for its support in this research. We thank F. Zhang for building the website for the software tool GCTB. This research was supported by the Australian Research Council (DP160101343, DP160101056, DP160103860, and DP160102400), the Australian National Health and Medical Research Council (1107258, 1078901, 1078037, 1083656, 1078399, 1046880, and 1113400), the US National Institutes of Health (MH100141, GM099568, ES025052, and AG042568), and the Sylvia & Charles Viertel Charitable Foundation (Senior Medical Research Fellowship). R.d.V. acknowledges funding from an ERC consolidator grant (647648 EdGe, awarded to Philipp Koellinger). This study makes use of data from dbGaP (accessions: phs000090 and phs000091), UK10K project (EGA accessions: EGAS00001000108 and EGAS00001000090), and UK Biobank Resource (application number: 12514). A full list of acknowledgements for these datasets can be found in part 19 of the Supplementary Note.

Funders	Funder number
Australian National Health and Medical Research Council
US National Institutes of Health
National Institutes of Health	ES025052, GM099568, MH100141, AG042568
Sylvia and Charles Viertel Charitable Foundation
Horizon 2020 Framework Programme	692145, 647648
European Research Council
Australian Research Council	DP160101343, DP160102400, DP160101056, DP160103860
National Health and Medical Research Council	1078901, 1107258, 1078399, 1083656, 1113400, 1046880, 1078037

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Signatures of negative selection in the genetic architecture of human complex traitsFinal published version, 4.53 MBLicence: Article 25fa Dutch Copyright Act

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Zeng, J., De Vlaming, R., Wu, Y., Robinson, M. R., Lloyd-Jones, L. R., Yengo, L., Yap, C. X., Xue, A., Sidorenko, J., McRae, A. F., Powell, J. E., Montgomery, G. W., Metspalu, A., Esko, T., Gibson, G., Wray, N. R., Visscher, P. M., & Yang, J. (2018). Signatures of negative selection in the genetic architecture of human complex traits. Nature Genetics, 50(5), 746-753. https://doi.org/10.1038/s41588-018-0101-4

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title = "Signatures of negative selection in the genetic architecture of human complex traits",

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 (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 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.",

author = "Jian Zeng and {De Vlaming}, Ronald and Yang Wu and Robinson, {Matthew R.} and Lloyd-Jones, {Luke R.} and Loic Yengo and Yap, {Chloe X.} and Angli Xue and Julia Sidorenko and McRae, {Allan F.} and Powell, {Joseph E.} and Montgomery, {Grant W.} and Andres Metspalu and Tonu Esko and Greg Gibson and Wray, {Naomi R.} and Visscher, {Peter M.} and Jian Yang",

year = "2018",

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Zeng, J, De Vlaming, R, Wu, Y, Robinson, MR, Lloyd-Jones, LR, Yengo, L, Yap, CX, Xue, A, Sidorenko, J, McRae, AF, Powell, JE, Montgomery, GW, Metspalu, A, Esko, T, Gibson, G, Wray, NR, Visscher, PM & Yang, J 2018, 'Signatures of negative selection in the genetic architecture of human complex traits', Nature Genetics, vol. 50, no. 5, pp. 746-753. https://doi.org/10.1038/s41588-018-0101-4

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T1 - Signatures of negative selection in the genetic architecture of human complex traits

AU - Zeng, Jian

AU - De Vlaming, Ronald

AU - Wu, Yang

AU - Robinson, Matthew R.

AU - Lloyd-Jones, Luke R.

AU - Yengo, Loic

AU - Yap, Chloe X.

AU - Xue, Angli

AU - Sidorenko, Julia

AU - McRae, Allan F.

AU - Powell, Joseph E.

AU - Montgomery, Grant W.

AU - Metspalu, Andres

AU - Esko, Tonu

AU - Gibson, Greg

AU - Wray, Naomi R.

AU - Visscher, Peter M.

AU - Yang, Jian

PY - 2018/5

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N2 - 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 (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 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.

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

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