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

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 strat-egy 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 asso-ciated 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.

Automated summary

This study demonstrates the use of human-induced pluripotent stem cells (hiPSCs) to link human genetics with viral infectivity. It identifies a cis-regulatory region of the NDUFA4 gene associated with susceptibility to Zika virus infection. Loss of NDUFA4 reduces sensitivity to multiple viral infections, and mechanistic studies reveal that loss/reduction of NDUFA4 induces mitochondrial stress and upregulation of interferon signaling.