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. 2021 Mar;591(7848):92-98.
doi: 10.1038/s41586-020-03065-y. Epub 2020 Dec 11.

Genetic mechanisms of critical illness in COVID-19

Erola Pairo-Castineira #  1   2 , Sara Clohisey #  1 , Lucija Klaric #  2 , Andrew D Bretherick #  2 , Konrad Rawlik #  1 , Dorota Pasko  3 , Susan Walker  3 , Nick Parkinson  1 , Max Head Fourman  1 , Clark D Russell  1   4 , James Furniss  1 , Anne Richmond  2 , Elvina Gountouna  5 , Nicola Wrobel  6 , David Harrison  7 , Bo Wang  1 , Yang Wu  8 , Alison Meynert  2 , Fiona Griffiths  1 , Wilna Oosthuyzen  1 , Athanasios Kousathanas  3 , Loukas Moutsianas  3 , Zhijian Yang  9 , Ranran Zhai  9 , Chenqing Zheng  9 , Graeme Grimes  2 , Rupert Beale  10 , Jonathan Millar  1 , Barbara Shih  1 , Sean Keating  11 , Marie Zechner  1 , Chris Haley  1 , David J Porteous  5 , Caroline Hayward  2   5 , Jian Yang  12   13 , Julian Knight  14 , Charlotte Summers  15 , Manu Shankar-Hari  16   17 , Paul Klenerman  14 , Lance Turtle  18 , Antonia Ho  19 , Shona C Moore  18 , Charles Hinds  20 , Peter Horby  21 , Alistair Nichol  22   23   24 , David Maslove  25 , Lowell Ling  26 , Danny McAuley  27   28 , Hugh Montgomery  29 , Timothy Walsh  11 , Alexandre C Pereira  30   31 , Alessandra Renieri  32   33 ; GenOMICC Investigators; ISARIC4C Investigators; COVID-19 Human Genetics Initiative; 23andMe Investigators; BRACOVID Investigators; Gen-COVID Investigators; Xia Shen  9   34   35 , Chris P Ponting  2 , Angie Fawkes  6 , Albert Tenesa  1   2   34 , Mark Caulfield  3   20 , Richard Scott  3   36 , Kathy Rowan  7 , Lee Murphy  6 , Peter J M Openshaw  37   38 , Malcolm G Semple  18   39 , Andrew Law  1 , Veronique Vitart  2 , James F Wilson  2   34 , J Kenneth Baillie  40   41   42
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Free article

Genetic mechanisms of critical illness in COVID-19

Erola Pairo-Castineira et al. Nature. 2021 Mar.
Free article

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.

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