ArticleGenome medicine2023
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
Erratum issuedOpen access · goldAbstract read
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Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 58 papers.
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58citing papers in PubMed
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Who cites it
58 citing papers in PubMed, 77 citations in OpenAlex.
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- Rare genetic variant risks in patients with sepsis-associated acute respiratory distress syndrome.Respiratory research · 2026Article
- Genetic contribution to severe COVID-19 in adults under 60 years without major comorbidities in the German National Pandemic Cohort Network (NAPKON).Human genomics · 2026Article
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Corrections and comments
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Authors and funding
130 authors at 20 institutions in 25 countries.
Daniela MatuozzoLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Estelle TalouarnLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Astrid MarchalLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Peng ZhangSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Jeremy ManryLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Yoann SeeleuthnerLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Yu ZhangLaboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, USA.
Alexandre BolzeHelix, San Mateo, CA, USA.
Matthieu ChaldebasSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Baptiste MilisavljevicSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Adrian GervaisLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Paul BastardLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Takaki AsanoSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Lucy BizienLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Federica BarzaghiDepartment of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Hassan AbolhassaniDepartment of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
Ahmad Abou TayounGenomics Center of Excellence, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.
Alessandro AiutiSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan, Italy.
Ilad Alavi DarazamInfectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Luis M AllendeImmunology Department, University Hospital 12 de Octubre, Research Institute imas12 and Complutense University, Madrid, Spain.
Rebeca Alonso-AriasImmunology Department, Hospital Universitario Central de Asturias; Health Research Institute of Principality of Asturias, Oviedo, Spain.
Andrés Augusto AriasSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Gokhan AytekinDeparment of Internal Medicine, Division of Allergy and Immunology, Konya City Hospital, Konya, Turkey.
Peter BergmanDepartment of Infectious Diseases, The Immunodeficiency Unit, Karolinska University Hospital, Stockholm, Sweden.
Simone BondesanClinical Genomics, IRCSS San Raffaele Scientific Institute, Milan, Italy.
Yenan T BrycesonDepartment of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
Ingrid G BustosUniversidad de La Sabana, Chía, Colombia.
Oscar Cabrera-MaranteInstitute of Biomedical Research of IdiPAZ, University Hospital "La Paz", Madrid, Spain.
Sheila CarcelUnidad de Gestión Clínica de Cuidados Intensivos, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.
Paola CarreraClinical Genomics, IRCSS San Raffaele Scientific Institute, Milan, Italy.
Giorgio CasariDivision of Genetics and Cell Biology, Genome-Phenome Relationship, San Raffaele Hospital, Milan, Italy.
Khalil ChaïbiIntensive Care Unit Department, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France.
Roger ColobranJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.
Antonio Condino-NetoDepartment of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Laura E CovillDepartment of Medicine, Centre for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
Ottavia M DelmonteLaboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, USA.
Loubna El ZeinBiology Department, Lebanese University, Beirut, Lebanon.
Carlos FloresGenomics Division, Institute of Technology and Renewable Energies (ITER), Santa Cruz de Tenerife, Spain.
Peter K GregersenFeinstein Institute for Medical Research, Northwell Health USA, Manhasset, NY, USA.
Marta GutCNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Filomeen HaerynckDepartment of Internal Diseases and Pediatrics, Primary Immune Deficiency Research Laboratory, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent, Belgium.
Rabih HalwaniResearch Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
Selda HancerliDepartment of Pediatrics (Infectious Diseases), Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Lennart HammarströmDepartment of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
Nevin HatipoğluPediatric Infectious Diseases Unit, Bakirkoy Dr Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
Adem KarbuzDepartment of Pediatric Infectious Disease, Dr. Cemil Tascioglu City Hospital, Istanbul, Turkey.
Sevgi KelesMeram Medical Faculty, Pediatric Infectious Diseases Department, Necmettin Erbakan University, Konya, Turkey.
Christèle KyhengDepartment of General Paediatrics, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, University of Paris Saclay, Le Kremlin-Bicêtre, France.
Rafael Leon-LopezUnidad de Gestión Clínica de Cuidados Intensivos, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba (UCO), Córdoba, Spain.
Jose Luis FrancoPrimary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEA, Medellin, 050010, Colombia.
Davood MansouriThe Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Javier Martinez-PicadoIrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias I Pujol (IGTP), Badalona, Spain.
Ozge Metin AkcanMeram Medical Faculty, Pediatric Infectious Diseases Department, Necmettin Erbakan University, Konya, Turkey.
Isabelle MigeotteCentre de Génétique Humaine de L'Université Libre de Bruxelles, Hôpital Erasme, Brussels, Belgium.
Pierre-Emmanuel MorangeLaboratory of Haematology, La Timone Hospital, Marseille, France.
Guillaume MorelleDepartment of General Paediatrics, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, University of Paris Saclay, Le Kremlin-Bicêtre, France.
Andrea Martin-NaldaJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.
Giuseppe NovelliDepartment of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
Tayfun OzcelikDepartment of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
Figen PalabiyikPediatric Infectious Diseases Unit, Bakirkoy Dr Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
Qiang Pan-HammarströmDepartment of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
Rebeca Pérez de DiegoLaboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, University Hospital "La Paz", Madrid, Spain.
Laura Planas-SerraNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
Daniel E PleguezueloImmunology Department, University Hospital 12 de Octubre, Research Institute imas12 and Complutense University, Madrid, Spain.
Carolina PrandoFaculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil.
Aurora PujolCatalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
Luis Felipe ReyesUniversidad de La Sabana, Chía, Colombia.
Jacques G RivièreJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.
Carlos Rodriguez-GallegoDepartment of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, Las Palmas de Gran Canaria, Spain.
Julian RojasPrimary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia UDEA, Medellin, 050010, Colombia.
Patrizia Rovere-QueriniVita-Salute San Raffaele University, Milan, Italy.
Agatha SchlüterNeurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
Mohammad ShahrooeiSpecialized Immunology Laboratory of Dr Shahrooei, Sina Medical Complex, Ahvaz, Iran.
Ali SobhDepartment of Pediatrics, Mansoura University Children's Hospital, Mansoura University Faculty of Medicine, Mansoura, Egypt.
Pere Soler-PalacinJeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Catalonia, Spain.
Yacine Tandjaoui-LambiotteHypoxia and Lung, INSERM U1272, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny, France.
Imran TipuDepartment of Life Sciences, School of Science, University of Management and Technology, Lahore, Pakistan.
Cristina TresoldiDivision of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.
Jesus TroyaDepartment of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain.
Diederik van de BeekDepartment of Neurology, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands.
Mayana ZatzBiosciences Institute, University of São Paulo, São Paulo, Brazil.
Pawel ZawadzkiGordion Bioscience Inc, Cambridge, MA, USA.
Saleh Zaid Al-MuhsenDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
Mohammed Faraj AlosaimiDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
Fahad M AlsohimeDepartment of Pediatrics, Immunology Research Laboratory, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
Hagit Baris-FeldmanThe Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Manish J ButteDepartments of Pediatrics and Microbiology, Immunology, and Molecular Genetics, Division of Immunology, Allergy, and Rheumatology, University of California Los Angeles, Los Angeles, CA, USA.
Stefan N ConstantinescuLudwig Institute for Cancer Research, Brussels, Belgium.
Megan A CooperDepartment of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. Louis, St. Louis, MO, USA.
Clifton L DalgardThe American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, USA.
Jacques FellaySchool of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
James R HeathInstitute for Systems Biology, Seattle, WA, USA.
Yu-Lung LauDepartment of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Richard P LiftonLaboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA.
Tom ManiatisZukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
Trine H MogensenDepartment of Biomedicine, Aarhus University, Aarhus, Denmark.
Horst von BernuthDepartment of Paediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
Alban LermineLaboratoire de Biologie Médicale Multisites Seqoia, MG2025, MG2025, Paris, France.
Michel VidaudLaboratoire de Biologie Médicale Multisites Seqoia, MG2025, MG2025, Paris, France.
Anne BolandUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France.
Jean-François DeleuzeUniversité Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France.
Robert NussbaumInvitae, San Francisco, CA, USA.
Amanda Kahn-KirbyInvitae, San Francisco, CA, USA.
France MentreUnité de Recherche Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.
Sarah TubianaCentre d'Investigation Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.
Guy GorochovSorbonne Université, INSERM Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Département d'immunologie Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Florence TubachSorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Unité de Recherche Clinique PSL-CFX , CIC-1901, Paris, France.
Pierre HausfaterEmergency Department, Hôpital Pitié-Salpêtrière, APHP-Sorbonne Université, Paris, France.
COVID Human Genetic Effort
COVIDeF Study Group
French COVID Cohort Study Group
CoV-Contact Cohort
COVID-STORM Clinicians
COVID Clinicians
Orchestra Working Group
Amsterdam UMC Covid-19 Biobank
NIAID-USUHS COVID Study Group
Isabelle MeytsDepartment of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
Shen-Ying ZhangLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Luigi D NotarangeloLaboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, MA, USA.
Stephanie Boisson-DupuisLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Helen C SuLaboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, Bethesda, MD, USA.
Bertrand BoissonLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Emmanuelle JouanguyLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Jean-Laurent Casanova *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France. casanova@rockefeller.edu.
Qian Zhang *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Laurent Abel *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Aurélie Cobat *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France. aurelie.cobat@inserm.fr.ORCID http://orcid.org/0000-0001-7209-6257
Inserm · FRCommissariat à l'Énergie Atomique et aux Énergies Alternatives · FRVita-Salute San Raffaele University · ITUniversitat Autònoma de Barcelona · ESAssistance Publique – Hôpitaux de Paris · FRHelix (United States) · USHoward Hughes Medical Institute · USKU Leuven · BERockefeller University · USInstituto de Salud Carlos III · ESUniversidad de Antioquia · COUniversité Paris-Saclay · FRYale University · USKarolinska Institutet · SEKing Saud University · SANational Institutes of Health · USHospital Universitario Infanta Leonor · ESInstituto Maimónides de Investigación Biomédica de Córdoba · ESInvitae (United States) · USResearch Institute Hospital 12 de Octubre · ES
Funding
Infectious Diseases Research Technologies Core - BethesdaZICAI001051 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI CHERRY, JAMES · 2009 to 2025
$226.1MTRANSFORMING TRANSLATIONAL SCIENCE AND EDUCATION TO BENEFIT HUMAN HEALTHUL1RR024143 · NCRR · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY · 2006 to 2011
$49.1MDeveloping, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MYale Center for Mendelian GenomicsUM1HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2016 to 2020
$14.8MHost factors contributing to susceptibility to COVID-19 diseaseZIAAI001265 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI SU, HELEN CHUN-HUI · 2020 to 2025
$9.5MMonogenic basis of resistance to SARS-CoV2 and predisposition to severe COVID-19R01AI088364 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI Jean-Laurent Casanova, Shen-Ying Zhang · 2010 to 2026
$8.7MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MInborn errors of immunity in patients with life-threatening COVID-19R01AI163029 · NIAID · ROCKEFELLER UNIVERSITY · PI CASANOVA, JEAN-LAURENT, ZHANG, QIAN · 2021 to 2025
$3.7MCharacterization of host immune responses to SARS-CoV-2ZIAAI001270 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI NOTARANGELO, LUIGI · 2020 to 2025
$1.2MHigh Performance Computing Instrumentation for the Yale Center for Genome AnalysiS10OD018521 · OD · YALE UNIVERSITY · PI MANE, SHRIKANT M · 2015 to 2015
$890kHoward Hughes Medical InstituteMedical Research Council MR/S032304/1NCATS NIH HHS UL1 TR001866NCRR NIH HHS UL1 RR024143NHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006504NIAID NIH HHS R01 AI088364NIAID NIH HHS R01 AI163029NIH HHS S10 OD018521
Abstract
backgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.
methodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.
resultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10
conclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Indexed as
COVID-19Interferon Type IAdultAutoantibodiesHumansMiddle AgedSARS-CoV-2Toll-Like Receptor 3Toll-Like Receptor 7Young AdultAutoantibodiesInterferon Type IToll-Like Receptor 3Toll-Like Receptor 7COVID-19ImmunityRare variantsType I interferon
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