ArticleCell stem cell2022
A human iPSC-array-based GWAS identifies a virus susceptibility locus in the NDUFA4 gene and functional variants.
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Article in Cell stem cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14citing papers in PubMed
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14 citing papers in PubMed, 18 citations in OpenAlex.
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Authors and funding
37 authors at 12 institutions in 3 countries.
Yuling HanDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Lei TanDepartment 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.
Ting ZhouDepartment 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.
Liuliu YangDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Lucia CarrauDepartment of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
Lauretta A LackoDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Mohsan SaeedLaboratory 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.
Jiajun ZhuDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Zeping ZhaoDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Benjamin E Nilsson-PayantDepartment of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
Filipe Tenorio Lira NetoDepartment of Urology, Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Brazil.
Clare CahirDepartment 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.
Alice Maria GianiDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Jin Chou ChaiDepartment of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Yang LiDepartment of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Xue DongDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Dorota MoroziewiczThe New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
NYSCF Global Stem Cell Array TeamThe New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
Daniel PaullThe New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
Tuo ZhangGenomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
Soyeon KooDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA; Weill Cornell Neuroscience PhD Program, New York, NY, USA.
Christina TanDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Ron DanzigerDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Qian BaDepartment 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.
Lingling FengDepartment 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.
Zhengming ChenDepartment of Population Health Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
Aaron ZhongStem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Gilbert J WiseDepartment of Urology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
Jenny Z XiangGenomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
Hui WangSchool of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Robert E SchwartzDivision 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.
Benjamin R tenOeverDepartment of Microbiology, New York University, 430 E 29th Street, New York, NY 10016, USA.
Scott A NoggleThe New York Stem Cell Foundation Research Institute, 619 West 54th Street, 3rd Floor, New York, NY 10019, USA.
Charles M RiceLaboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Qibin QiDepartment of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Todd EvansDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Shuibing ChenDepartment of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
Cornell University · USAlbert Einstein College of Medicine · USNew York Stem Cell Foundation · USNew York University · USMemorial Sloan Kettering Cancer Center · USShanghai Jiao Tong University · CNBoston University · USInstituto de Medicina Integral Professor Fernando Figueira · BRRockefeller University · USShenzhen Institutes of Advanced Technology · CNTri-Institutional PhD Program in Chemical Biology · USWeill Cornell Medicine · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MUnraveling yellow fever 17D vaccine attenuation: The role of type I interferon and innate immunityR01AI124690 · NIAID · ROCKEFELLER UNIVERSITY · PI Charles M Rice · 2016 to 2026
$8.3MType I interferon-stimulated genes and the antiviral immune responseR01AI091707 · NIAID · ROCKEFELLER UNIVERSITY · PI RICE, CHARLES M · 2011 to 2020
$5.5MDetermining the Intrinsic and Environmental Signal Contributing to Early T1D ProgressionU01DK127777 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING, PARKER, STEPHEN CJ · 2020 to 2023
$3.0MMetallothionein 1E as a Central Regulator of Human Pancreatic Beta Cell Function and SurvivalR01DK119667 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING · 2019 to 2022
$2.5MDiscovery of T1DM Associated Functional Variants in Human Pancreatic Beta Cell Development and SurvivalDP3DK111907 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING · 2016 to 2016
$2.0MA High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell ProliferationR01DK124463 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING · 2020 to 2023
$1.7MDecode the Impact of SARS-CoV-2 on Human PancreasR01DK130454 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING, LIM, JEAN KYOU · 2021 to 2023
$1.3MA High Throughput Screening to Identify Compounds Rescuing Human Pancreatic Beta Cell Function in Diabetic ConditionsR01DK116075 · NIDDK · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHEN, SHUIBING · 2018 to 2020
$1.3MEffect of Pre- and Peri-Implantation Zika Virus Infection on Fetal DevelopmentF32HD096810 · NICHD · WEILL MEDICAL COLL OF CORNELL UNIV · PI LACKO, LAURETTA A. · 2019 to 2021
$212kNCI NIH HHS P30 CA008748NIAID NIH HHS R01 AI091707NIAID NIH HHS R01 AI124690NICHD NIH HHS F32 HD096810NIDDK NIH HHS DP3 DK111907NIDDK NIH HHS R01 DK116075NIDDK NIH HHS R01 DK119667NIDDK NIH HHS R01 DK124463NIDDK NIH HHS R01 DK130454NIDDK NIH HHS U01 DK127777
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.
Indexed as
COVID-19DengueElectron Transport Complex IVZika Virus InfectionAllelesDNA, MitochondrialGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansInduced Pluripotent Stem CellsInterferon Type IPolymorphism, Single NucleotideSARS-CoV-2Zika VirusDNA, MitochondrialElectron Transport Complex IVInterferon Type INDUFA4 protein, humanDengue Virusgenome-wide association studyiPSC arrayisogenic hiPSC linesmtDNANDUFA4risk alleleSARS-CoV-2single-nucleotide polymorphismtype I interferon
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