TY - JOUR
T1 - Genetic mechanisms of critical illness in COVID-19
AU - GEN-COVID Contributors
AU - The GenOMICC Investigators
AU - GenOMICC Consortium
AU - GenOMICC co-investigators
AU - Central management and laboratory team
AU - Data Analysis Team
AU - The ISARIC4C Investigators
AU - ISARIC4C Consortium
AU - ISARIC co-investigators
AU - Project Management Team
AU - Data Architecture Team
AU - Data Analysis and Management Team
AU - The COVID-19 Human Genetics Initiative
AU - HGI Consortium (COVID-19 Host Genetics Initiative)
AU - 23andMe investigators
AU - The 23andMe COVID-19 Team
AU - BRACOVID Investigators
AU - Gen-COVID Investigators
AU - Pairo-Castineira, Erola
AU - Clohisey, Sara
AU - Klaric, Lucija
AU - Bretherick, Andrew D.
AU - Rawlik, Konrad
AU - Pasko, Dorota
AU - Walker, Susan
AU - Parkinson, Nick
AU - Fourman, Max Head
AU - Russell, Clark D.
AU - Furniss, James
AU - Richmond, Anne
AU - Gountouna, Elvina
AU - Wrobel, Nicola
AU - Harrison, David
AU - Wang, Bo
AU - Wu, Yang
AU - Meynert, Alison
AU - Griffiths, Fiona
AU - Oosthuyzen, Wilna
AU - Kousathanas, Athanasios
AU - Moutsianas, Loukas
AU - Yang, Zhijian
AU - Zhai, Ranran
AU - Zheng, Chenqing
AU - Grimes, Graeme
AU - Beale, Rupert
AU - Millar, Jonathan
AU - Shih, Barbara
AU - Keating, Sean
AU - Zechner, Marie
AU - Haley, Chris
AU - Porteous, David J.
AU - Hayward, Caroline
AU - Yang, Jian
AU - Knight, Julian
AU - Summers, Charlotte
AU - Shankar-Hari, Manu
AU - Klenerman, Paul
AU - Turtle, Lance
AU - Ho, Antonia
AU - Moore, Shona C.
AU - Hinds, Charles
AU - Horby, Peter
AU - Nichol, Alistair
AU - Maslove, David
AU - Ling, Lowell
AU - McAuley, Danny
AU - Montgomery, Hugh
AU - Faulkner, M.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/3/4
Y1 - 2021/3/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85102602000
U2 - 10.1038/s41586-020-03065-y
DO - 10.1038/s41586-020-03065-y
M3 - Article
C2 - 33307546
AN - SCOPUS:85102602000
SN - 0028-0836
VL - 591
SP - 92
EP - 98
JO - Nature
JF - Nature
IS - 7848
ER -