1. Academic Validation
  2. A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants

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

  • Cell Stem Cell. 2022 Oct 6;29(10):1475-1490.e6. doi: 10.1016/j.stem.2022.09.008.
Yuling Han 1 Lei Tan 2 Ting Zhou 3 Liuliu Yang 1 Lucia Carrau 4 Lauretta A Lacko 1 Mohsan Saeed 5 Jiajun Zhu 1 Zeping Zhao 1 Benjamin E Nilsson-Payant 4 Filipe Tenorio Lira Neto 6 Clare Cahir 7 Alice Maria Giani 1 Jin Chou Chai 8 Yang Li 8 Xue Dong 1 Dorota Moroziewicz 9 NYSCF Global Stem Cell Array Team 9  Daniel Paull 9 Tuo Zhang 10 Soyeon Koo 11 Christina Tan 1 Ron Danziger 1 Qian Ba 12 Lingling Feng 13 Zhengming Chen 14 Aaron Zhong 15 Gilbert J Wise 16 Jenny Z Xiang 10 Hui Wang 17 Robert E Schwartz 18 Benjamin R tenOever 4 Scott A Noggle 9 Charles M Rice 19 Qibin Qi 8 Todd Evans 1 Shuibing Chen 20
Affiliations

Affiliations

  • 1 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • 2 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 3 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
  • 4 Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
  • 5 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA 02118, USA.
  • 6 Department of Urology, Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil.
  • 7 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; The Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.
  • 8 Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • 9 The New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
  • 10 Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
  • 11 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Weill Cornell Neuroscience PhD Program, New York, NY, USA.
  • 12 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 13 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, China.
  • 14 Department of Population Health Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • 15 Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
  • 16 Department of Urology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • 17 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 18 Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • 19 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • 20 Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
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.

Figures
Products