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

Yuling Han; Lei Tan; Ting Zhou; Liuliu Yang; Lucia Carrau; Lauretta A Lacko; Mohsan Saeed; Jiajun Zhu; Zeping Zhao; Benjamin E Nilsson-Payant; Filipe Tenorio Lira Neto; Clare Cahir; Alice Maria Giani; Jin Chou Chai; Yang Li; Xue Dong; Dorota Moroziewicz; NYSCF Global Stem Cell Array Team; Daniel Paull; Tuo Zhang; Soyeon Koo; Christina Tan; Ron Danziger; Qian Ba; Lingling Feng; Zhengming Chen; Aaron Zhong; Gilbert J Wise; Jenny Z Xiang; Hui Wang; Robert E Schwartz; Benjamin R tenOever; Scott A Noggle; Charles M Rice; Qibin Qi; Todd Evans; Shuibing Chen

doi:10.1016/j.stem.2022.09.008

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.

Authors

Yuling Han¹, Lei Tan², Ting Zhou³, Liuliu Yang¹, Lucia Carrau⁴, Lauretta A Lacko¹, Mohsan Saeed⁵, Jiajun Zhu¹, Zeping Zhao¹, Benjamin E Nilsson-Payant⁴, Filipe Tenorio Lira Neto⁶, Clare Cahir⁷, Alice Maria Giani¹, Jin Chou Chai⁸, Yang Li⁸, Xue Dong¹, Dorota Moroziewicz⁹; NYSCF Global Stem Cell Array Team⁹; Daniel Paull⁹, Tuo Zhang¹⁰, Soyeon Koo¹¹, Christina Tan¹, Ron Danziger¹, Qian Ba¹², Lingling Feng¹³, Zhengming Chen¹⁴, Aaron Zhong¹⁵, Gilbert J Wise¹⁶, Jenny Z Xiang¹⁰, Hui Wang¹⁷, Robert E Schwartz¹⁸, Benjamin R tenOever⁴, Scott A Noggle⁹, Charles M Rice¹⁹, Qibin Qi⁸, Todd Evans¹, Shuibing Chen²⁰

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
COVID-19* / genetics
DNA, Mitochondrial / metabolism
Dengue* / genetics
Electron Transport Complex IV* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Induced Pluripotent Stem Cells / metabolism
Interferon Type I / metabolism
Polymorphism, Single Nucleotide
SARS-CoV-2
Zika Virus
Zika Virus Infection* / genetics

Substances

DNA, Mitochondrial
Electron Transport Complex IV
Interferon Type I
NDUFA4 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding