Evidence map›Paper›PMID 35943608›Full record

ArticleHuman genetics2022

Locus-level antagonistic selection shaped the polygenic architecture of human complex diseases.

Weichen Song, Kai Yuan, Zhe Liu, Wenxiang Cai, Jue Chen, Shunying Yu, Min Zhao, Guan Ning Lin

Abstract read
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In one paragraph

Article in Human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed
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1 · What the graph read from it

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3 · Its place in the literature

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1 citing paper in PubMed.

  1. Review
4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Weichen SongShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.ORCID http://orcid.org/0000-0003-3197-6236
Kai YuanShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Zhe LiuShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Wenxiang CaiShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Jue ChenShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Shunying YuShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Min ZhaoShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. drminzhao@smhc.org.cn.
Guan Ning LinShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. nickgnlin@sjtu.edu.cn.

Funding

National Natural Science Foundation of China 81971292
6 · The paper itself

Abstract

backgroundWe aimed to evaluate the potential role of antagonistic selection in polygenic diseases: if one variant increases the risk of one disease and decreases the risk of another disease, the signals of genetic risk elimination by natural selection will be distorted, which leads to a higher frequency of risk alleles.

methodsWe applied local genetic correlations and transcriptome-wide association studies to identify genomic loci and genes adversely associated with at least two diseases. Then, we used different population genetic metrics to measure the signals of natural selection for these loci and genes.

resultsFirst, we identified 2120 cases of antagonistic pleiotropy (negative local genetic correlation) among 87 diseases in 716 genomic loci (antagonistic loci). Next, by comparing with non-antagonistic loci, we observed that antagonistic loci explained an excess proportion of disease heritability (median 6%), showed enhanced signals of balancing selection, and reduced signals of directional polygenic adaptation. Then, at the gene expression level, we identified 31,991 cases of antagonistic pleiotropy among 98 diseases at 4368 genes. However, evidence of altered signals of selection pressure and heritability distribution at the gene expression level is limited.

conclusionWe conclude that antagonistic pleiotropy is widespread among human polygenic diseases, and it has distorted the evolutionary signal and genetic architecture of diseases at the locus level.

Indexed as

Multifactorial InheritanceSelection, GeneticAdaptation, PhysiologicalAllelesGenetics, PopulationHumans

Identifiers

PMID35943608

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