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

作者：Han, Yuling; Tan, Lei; Zhou, Ting; Yang, Liuliu; Carrau, Lucia; Lacko, Lauretta A.; Saeed, Mohsan; Zhu, Jiajun; Zhao, Zeping; Nilsson-Payant, Benjamin E.; Neto, Filipe Tenorio Lira; Cahir, Clare; Giani, Alice Maria; Chai, Jin Chou; Li, Yang; Dong, Xue; Moroziewicz, Dorota; Paull, Daniel; Zhang, Tuo; Koo, Soyeon; Tan, Christina; Danziger, Ron; Ba, Qian; Feng, Lingling; Chen, Zhengming; Zhong, Aaron; Wise, Gilbert J.; Xiang, Jenny Z.; Wang, Hui; Schwartz, Robert E.; tenOever, Benjamin R.

来源：Cell Stem Cell, 2022, 29(10): 1475-+.

DOI：10.1016/j.stem.2022.09.008

• CYTOCHROME-C-OXIDASE
• NEURAL PROGENITORS
• COMPLEX-IV
• DIFFERENTIATION
• INFECTION
• INHIBITION
• ORGANOIDS
• SUBUNIT
• CELLS

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.

• 单位
  河北医科大学; 中国科学院; 上海交通大学