A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants. Academic Article uri icon

Overview

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.

authors

publication date

  • October 6, 2022

Research

keywords

  • COVID-19
  • Dengue
  • Electron Transport Complex IV
  • Zika Virus Infection

Identity

PubMed Central ID

  • PMC9550219

Scopus Document Identifier

  • 85050357074

Digital Object Identifier (DOI)

  • 10.1038/s41422-018-0071-1

PubMed ID

  • 36206731

Additional Document Info

volume

  • 29

issue

  • 10