Genetic mechanisms of critical illness in COVID-19
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Abstract
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.
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The record
- Venue
- Nature
- Topic
- RNA modifications and cancer
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Kingston Health Sciences CentreQueen's University
- Funders
- Barts and The London School of Medicine and DentistryChinese University of Hong KongGreat Ormond Street Hospital for ChildrenQueen's UniversitySun Yat-sen UniversityUniversity of QueenslandPublic Health EnglandQueen's University BelfastUniversity of GlasgowDepartment for International DevelopmentIntensive Care SocietyRosetrees TrustEuropean CommissionKing's College LondonParkinson's UKMedical Research CouncilDepartment of Health and Social CareQueen Mary University of LondonHealth Research BoardNational Institute for Health and Care ResearchScottish Funding CouncilBiotechnology and Biological Sciences Research CouncilUniversity College DublinImperial College Healthcare NHS TrustWellcome TrustUniversity College LondonCancer Research UKWestlake UniversityUniversity of OxfordNational Institute for Health Research Health Protection Research UnitUniversidade de São PauloUniversità degli Studi di SienaBarts CharityChief Scientist Office, Scottish Government Health and Social Care DirectorateScottish GovernmentMonash UniversityFrancis Crick InstituteAlder Hey Children's NHS Foundation TrustUK Research and InnovationResearch Councils UKImperial College LondonLifeArcKarolinska InstitutetBill and Melinda Gates Foundation
- Keywords
- BiologyGenome-wide association studyGeneticsGeneCandidate geneSingle-nucleotide polymorphismBioinformaticsGenotype
- Has abstract in OpenAlex
- yes