A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants

The NYSCF Global Stem Cell Array Team

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1475-1490.e6
JournalCell Stem Cell
Volume29
Issue number10
DOIs
StatePublished - Oct 6 2022

Keywords

  • Dengue Virus
  • genome-wide association study
  • iPSC array
  • isogenic hiPSC lines
  • mtDNA
  • NDUFA4
  • risk allele
  • SARS-CoV-2
  • single-nucleotide polymorphism
  • type I interferon

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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