Abstract
Background
We 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.
Methods
We 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.
Results
First, 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.
Conclusion
We 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.
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Data availability
All data analysed in this study were obtained from the public domain. Script used for this study will be made available at https://github.com/WeiCSong/antagSelection.
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Funding
The study was supported by the National Natural Science Foundation of China (No: 81971292 and 82150610506, G.N.L); The Natural Science Foundation of Shanghai (No: 21ZR1428600, G.N.L); Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (Grant No. 1610000043, G.N.L). We thank all researchers and consortiums that share their GWAS summary statistics with the scientific community.
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Song, W., Yuan, K., Liu, Z. et al. Locus-level antagonistic selection shaped the polygenic architecture of human complex diseases. Hum Genet 141, 1935–1947 (2022). https://doi.org/10.1007/s00439-022-02471-8
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DOI: https://doi.org/10.1007/s00439-022-02471-8