A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants PMID: 36206731

Target-related Cytokines

2026-09-23

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

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: [email protected].

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.