TY - JOUR
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, Nicholas
AU - Head Fourman, Max
AU - Russell, Clark D.
AU - Furniss, James
AU - Richmond, Anne
AU - Gountouna, Elvina
AU - Wrobel, Nicola
AU - Harrison, David A.
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 E.
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 C.
AU - Summers, Charlotte
AU - Shankar-Hari, Manu
AU - Klenerman, Paul
AU - Turtle, Lance C.W.
AU - Ho, Antonia
AU - Moore, Shona C.
AU - Hinds, Charles J.
AU - Horby, Peter W.
AU - Maslove, David M.
AU - Ling, Lowell
AU - McAuley, Daniel F.
AU - Montgomery, Hugh
AU - Walsh, Timothy
AU - Pereira, Alex
AU - Renieri, Alessandra
AU - The GenOMICC Investigators
AU - ISARIC4C Investigators
AU - The Covid-19 Human Genetics Initiative
AU - 23andMe Investigators
AU - BRACOVID Investigators
AU - Gen-COVID Investigators
AU - Shen, Xia
AU - Ponting, Chris P.
AU - Fawkes, Angie
AU - Tenesa, Albert
AU - Caulfield, Mark J.
AU - Scott, Richard H.
AU - Rowan, Kathryn M.
AU - Openshaw, Peter J.M.
AU - Semple, Malcolm G.
AU - Law, Andy
AU - Vitart, Veronique
AU - Wilson, James F.
AU - Baillie, J. Kenneth
PY - 2020
DA - December
TI - Genetic mechanisms of critical illness in Covid-19
JO - Nature
EP - 98
VL - 591
DO - http://dx.doi.org/10.1038/s41586-020-03065-y
AB - Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; 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. Large-scale randomised clinical trials will be essential before any change to clinical practice.
PB - Springer Nature
UR - http://eprints.gla.ac.uk/226569/
KW - Coronavirus (COVID-19)
ER