Genetic mechanisms of critical illness in COVID-19

Data analysis and management team, The COVID-19 Human Genetics Initiative, HGI Consortium (COVID-19 Host Genetics Initiative), 23andMe Investigators, The 23andMe COVID-19 Team, BRACOVID Investigators, Gen-COVID Investigators, GEN-COVID Contributors, The GenOMICC Investigators, GenOMICC Consortium, GenOMICC co-investigators, Central management and laboratory team, Data analysis team, The ISARIC4C Investigators, ISARIC4C Consortium, ISARIC co-investigators, Project management team, Data architecture team

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)92-98
Number of pages7
JournalNature
Volume591
Issue number7848
DOIs
Publication statusPublished - 4 Mar 2021

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