TY - JOUR

T1 - Genetic mechanisms of critical illness in COVID-19

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 - Walsh, Timothy

AU - Pereira, Alexandre C

AU - Renieri, Alessandra

AU - GenOMICC Investigators,

AU - ISARIC4C Investigators,

AU - 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

AU - Scott, Richard

AU - Rowan, Kathy

AU - Murphy, Lee

AU - Openshaw, Peter J M

AU - Semple, Malcolm G

AU - Law, Andrew

AU - Vitart, Veronique

AU - Wilson, James F

AU - Baillie, J Kenneth

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.

U2 - 10.1038/s41586-020-03065-y

DO - 10.1038/s41586-020-03065-y

M3 - Journal article

VL - 591

SP - 92

EP - 98

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7848

ER -