Locus-level antagonistic selection shaped the polygenic architecture of human complex diseases.
Hum Genet
; 141(12): 1935-1947, 2022 Dec.
Article
em En
| MEDLINE
| ID: mdl-35943608
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Seleção Genética
/
Herança Multifatorial
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Hum Genet
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China