A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.
Cell Stem Cell
; 29(10): 1475-1490.e6, 2022 10 06.
Article
em En
| MEDLINE
| ID: mdl-36206731
ABSTRACT
Population-based studies to identify disease-associated risk alleles typically require samples from a large number of individuals. Here, we report a human-induced pluripotent stem cell (hiPSC)-based screening strategy to link human genetics with viral infectivity. A genome-wide association study (GWAS) identified a cluster of single-nucleotide polymorphisms (SNPs) in a cis-regulatory region of the NDUFA4 gene, which was associated with susceptibility to Zika virus (ZIKV) infection. Loss of NDUFA4 led to decreased sensitivity to ZIKV, dengue virus, and SARS-CoV-2 infection. Isogenic hiPSC lines carrying non-risk alleles of SNPs or deletion of the cis-regulatory region lower sensitivity to viral infection. Mechanistic studies indicated that loss/reduction of NDUFA4 causes mitochondrial stress, which leads to the leakage of mtDNA and thereby upregulation of type I interferon signaling. This study provides proof-of-principle for the application of iPSC arrays in GWAS and identifies NDUFA4 as a previously unknown susceptibility locus for viral infection.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Complexo IV da Cadeia de Transporte de Elétrons
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Dengue
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Infecção por Zika virus
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COVID-19
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article