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Signatures of negative selection in the genetic architecture of human complex traits
Open accessPublished version of a preprint
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. BayesS estimates SNP-based heritability, polygenicity, and the relationship between effect size and minor allele frequency using genome-wide SNP data. Applying BayesS to UK Biobank data identifies signatures of natural selection for 23 complex traits.
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“Genomic features related to natural selection are enriched for loci associated with complex traits [1, 7–9].”
From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“In particular, background selection (i.e., the selective removal of deleterious alleles across the genome) appears to play a primary role in shaping the highly polygenic architecture of human traits and diseases [1, 7–9].”
From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“The relative contributions of common and rare variants indicate that, for many traits, particularly those with post-reproductive onset, purifying selection has had only limited effect45,56.”
From A brief history of human disease genetics (2020) · cites this paper as [56]
In the citing paper
“Given what we know now, common variants generally have small effects on disease risk (OR <1.15), and rare variants typically have larger effect sizes (>2.0), are more likely to be deleterious, and tend to be removed by natural selection (Fu et al., 2013; Nelson et al., 2012; Zeng et al., 2018).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Zeng et al., 2018
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Finding the missing heritability of complex diseases
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Self-citationGCTA: a tool for genome-wide complex trait analysis
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Self-citationAn integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
Self-citationThe Pfam protein families database: towards a more sustainable future
Finn, R. D., Coggill, P., Eberhardt, R. Y., Eddy, S. R., Mistry, J., Mitchell, A. L., Potter, S. C., Punta, M., Qureshi, M., Sangrador-Vegas, A., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1344 · Cited by 5,975
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Self-citationCommon SNPs explain a large proportion of the heritability for human height
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Self-citationGenome-wide association studies
Uffelmann, E., Huang, Q. Q., Munung, N. S., de Vries, J., Okada, Y., Martin, A. R., Martin, H. C., Lappalainen, T., & Posthuma, D. (2021) · Nature Reviews Methods Primers · doi:10.1038/s43586-021-00056-9 · Cited by 1,849
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Kichaev, G., Bhatia, G., Loh, P.-R., Gazal, S., Burch, K., Freund, M. K., Schoech, A., Pasaniuc, B., & Price, A. L. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.11.008 · Cited by 926
Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K. E., Zheng, Z., Yengo, L., Lloyd‐Jones, L. R., Sidorenko, J., Wu, Y., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04951-w · Cited by 897
Self-citationA brief history of human disease genetics
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., et al. (2020) · Nature · doi:10.1038/s41586-019-1879-7 · Cited by 697
Metadata
- Authors
- 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.
- Affiliations
- The University of Queensland (AU)
- University of Tartu (EE)
- Georgia Institute of Technology (US)
- Corresponding author
- Yang, Jian
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-04-16
- Volume
- 50
- Issue
- 5
- Pages
- 746-753
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2797293309
- Cited by
- 391
- References
- 99
- Citations by year
- 2026: 38 · 2025: 51 · 2024: 43 · 2023: 50 · 2022: 46 · 2021: 63 · 2020: 42 · 2019: 30 · 2018: 23
- FWCI
- 24.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- University of Queensland
- National Institutes of Health (GM 099568, AG042568)
- Medical Research Council (1107258, 1113400, 1078037, 1078901, MC_PC_17228)
- Australian Research Council (DP160103860, DP160101343, DP160102400, 1046880, 1113400, DP160101056)
- National Health and Medical Research Council (1083656, 1078399, 1113400, 1078901, 1107258, 1078037, 1046880)
- National Institute of Mental Health (R01MH100141)
- National Institute of General Medical Sciences (P01GM099568)
- National Institute of Environmental Health Sciences (R21ES025052)
- H2020 European Research Council (647648)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- negative selection, purifying selection, genetic architecture, complex traits, polygenicity, SNP-based heritability, natural selection signatures, educational attainment, anthropometric traits, cardiovascular traits, reproductive traits, UK Biobank
- MeSH terms
- Bayes Theorem, Gene Frequency, Genotype, Humans, Models, Genetic, Phenotype, Selection, Genetic, Linear Models, Quantitative Trait, Heritable, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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