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

Zeng, Jian, de Vlaming, Ronald, Wu, Yang, Robinson, Matthew R., Lloyd-Jones, Luke R., Yengo, Loic, Yap, Chloe X., Xue, Angli, Sidorenko, Julia, McRae, Allan F., Powell, Joseph E., Montgomery, Grant W., Metspalu, Andres, Esko, Tonu, Gibson, Greg, Wray, Naomi R., Visscher, Peter M. and Yang, Jian (2018) Signatures of negative selection in the genetic architecture of human complex traits. Nature Genetics, 50 5: 746-753. doi:10.1038/s41588-018-0101-4


Author Zeng, Jian
de Vlaming, Ronald
Wu, Yang
Robinson, Matthew R.
Lloyd-Jones, Luke R.
Yengo, Loic
Yap, Chloe X.
Xue, Angli
Sidorenko, Julia
McRae, Allan F.
Powell, Joseph E.
Montgomery, Grant W.
Metspalu, Andres
Esko, Tonu
Gibson, Greg
Wray, Naomi R.
Visscher, Peter M.
Yang, Jian
Title Signatures of negative selection in the genetic architecture of human complex traits
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2018-04-16
Year available 2018
Sub-type Article (original research)
DOI 10.1038/s41588-018-0101-4
Open Access Status Not yet assessed
Volume 50
Issue 5
Start page 746
End page 753
Total pages 8
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
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.
Formatted 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.
Keyword Genome-Wide Association
Body-Mass Index
Rare Variants
Human Height
Psychiatric-Disorders
Missing Heritability
Human-Populations
European Descent
Human Adaptation
Human-Evolution
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID DP160101343
1107258
MH100141
647648 EdGe
EGAS00001000108
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 1 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 1 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 25 Apr 2018, 10:09:31 EST