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A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.
Han, Yuling; Tan, Lei; Zhou, Ting; Yang, Liuliu; Carrau, Lucia; Lacko, Lauretta A; Saeed, Mohsan; Zhu, Jiajun; Zhao, Zeping; Nilsson-Payant, Benjamin E; Lira Neto, Filipe Tenorio; 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; Noggle, Scott A; Rice, Charles M; Qi, Qibin; Evans, Todd; Chen, Shuibing.
  • Han Y; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Tan L; 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.
  • Zhou T; 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.
  • Yang L; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Carrau L; Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
  • Lacko LA; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Saeed M; 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.
  • Zhu J; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Zhao Z; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Nilsson-Payant BE; Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
  • Lira Neto FT; Department of Urology, Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil.
  • Cahir C; 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.
  • Giani AM; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Chai JC; Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • Li Y; Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • Dong X; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Moroziewicz D; The New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
  • Paull D; The New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
  • Zhang T; Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
  • Koo S; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Weill Cornell Neuroscience PhD Program, New York, NY, USA.
  • Tan C; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Danziger R; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Ba Q; 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.
  • Feng L; 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.
  • Chen Z; Department of Population Health Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • Zhong A; Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
  • Wise GJ; Department of Urology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • Xiang JZ; Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
  • Wang H; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Schwartz RE; 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.
  • tenOever BR; Department of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
  • Noggle SA; The New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
  • Rice CM; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
  • Qi Q; Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • Evans T; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
  • Chen S; Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
Cell Stem Cell ; 29(10): 1475-1490.e6, 2022 10 06.
Article in English | MEDLINE | ID: covidwho-2061891
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Electron Transport Complex IV / Dengue / Zika Virus Infection / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Cell Stem Cell Year: 2022 Document Type: Article Affiliation country: J.stem.2022.09.008

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Electron Transport Complex IV / Dengue / Zika Virus Infection / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Humans Language: English Journal: Cell Stem Cell Year: 2022 Document Type: Article Affiliation country: J.stem.2022.09.008