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.
Keywords: Dengue Virus; NDUFA4; SARS-CoV-2; genome-wide association study; iPSC array; isogenic hiPSC lines; mtDNA; risk allele; single-nucleotide polymorphism; type I interferon.
【저자키워드】 SARS-CoV-2, Genome-wide association study, dengue virus, single-nucleotide polymorphism, type I interferon., risk allele, NDUFA4, iPSC array, isogenic hiPSC lines, mtDNA, 【초록키워드】 viral infection, Stress, SARS-COV-2 infection, susceptibility, SNPs, Infection, polymorphism, risk, type I interferon, Human genetics, sensitivity, Dengue, viral infectivity, Cluster, SNP, GWAS, Signaling, mitochondrial, Zika virus, locus, upregulation, screening strategy, non-risk allele, genome-wide association, ZIKV, Loss, Cell, identify, indicated, provide, cause, individuals, disease-associated, leakage of mtDNA, single-nucleotide, 【제목키워드】 susceptibility, virus, GWAS, locus, identify, functional variant,