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Genetic mechanisms of critical illness in Covid-19

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Erola Pairo-Castineira, Sara Clohisey, Lucija Klaric, Andrew D. Bretherick, Konrad Rawlik, Dorota Pasko, Susan Walker, Nick Parkinson, Max Head Fourman, Clark D. Russell, James Furniss, Anne Richmond, Elvina Gountouna, Nicola Wrobel, David Harrison, Bo Wang, Yang Wu, Alison Meynert, Fiona Griffiths, Wilna Oosthuyzen & 247 more Athanasios Kousathanas, Loukas Moutsianas, Zhijian Yang, Ranran Zhai, Chenqing Zheng, Graeme Grimes, Rupert Beale, Jonathan Millar, Barbara Shih, Sean Keating, Marie Zechner, Chris Haley, David J. Porteous, Caroline Hayward, Jian Yang, Julian Knight, Charlotte Summers, M. Shankar-Hari, Paul Klenerman, Lance Turtle, Antonia Ho, Shona C. Moore, Charles Hinds, Peter Horby, Alistair Nichol, David Maslove, Lowell Ling, Danny McAuley, Hugh Montgomery, Timothy Walsh, Alex Pereira, Alessandra Renieri, Johnny Millar, Tim Walsh, Peter J.M. Openshaw, Chris Ponting, Jen Meikle, Paul Finernan, Ellie Mcmaster, Andy Law, J. K. Baillie, Trevor Paterson, Tony Wackett, Ruth Armstrong, Richard Clark, Audrey Coutts, Lorna Donnelly, Tammy Gilchrist, Katarzyna Hafezi, Louise Macgillivray, Alan Maclean, Sarah McCafferty, Kirstie Morrice, Jane Weaver, Ceilia Boz, Ailsa Golightly, Mari Ward, Hanning Mal, Helen Szoor-McElhinney, Adam Brown, Ross Hendry, Andrew Stenhouse, Louise Cullum, Dawn Law, Sarah Law, Rachel Law, Maaike Swets, Nicky Day, Filip Taneski, Esther Duncan, Nicholas Parkinson, D. Collier, S. Wood, A. Zak, C. Borra, M. Matharu, P. May, Z. Alldis, O. Mitchelmore, R. Bowles, A. Easthorpe, F. Bibi, I. Lancoma-Malcolm, J. Gurasashvili, J. Pheby, J. Shiel, M. Bolton, M. Patel, M. Taylor, O. Zongo, P. Ebano, P. Harding, R. Astin-Chamberlain, Y. Choudhury, A. Cox, D. Kallon, M. Burton, R. Hall, S. Blowes, Z. Prime, J. Biddle, O. Prysyazhna, T. Newman, C. Tierney, J. Kassam, M. Ostermann, S. Campos, A. Bociek, R. Lim, N. Grau, T. O. Jones, C. Whitton, M. Marotti, G. Arbane, S. Bonner, K. Hugill, I. Welters, V. Waugh, J. Fernandez Roman, M. Lopez Martinez, A. Waite, O. Hamilton, S. Mulla, M. McPhail, J. Smith, J. K. Baillie, L. Barclay, C. McCulloch, L. McQuillan, J. Singleton, K. Priestley, N. Rea, M. Callaghan, G. Andrew, P. Hutton, A. Bashyal, N. Davidson, C. Summers, P. Polgarova, K. Stroud, N. Pathan, K. Elston, C. Battle, L. Newey, T. Rees, R. Harford, E. Brinkworth, M. Croft, N. Bandla, M. Gellamucho, H. Turner, A. Quinn, I. Hussain, R. Bradley, R. Griffiths, J. Scriven, A. Puxty, S. Cathcart, D. Salutous, K. Duffy, K. Puxty, A. Joseph, R. Herdman-Grant, R. Simms, A. Swain, A. Naranjo, R. Crowe, K. Sollesta, A. Loveridge, D. Baptista, E. Morino, M. Davey, D. Golden, J. Moreno Cuesta, A. Haldeos, D. Bakthavatsalam, M. Elhassan, K. Xavier, A. Ganesan, D. Purohit M. Abdelrazik, L. Akeroyd, S. Bano, M. Bromley, K. Sellick, L. Gurr, V. Nagarajan, P. Szedlak, J. Cupitt, E. Stoddard, L. Benham, N. Slawson, Z. Bradshaw, M. Caswell, S. Melling, P. Bamford, K. Cawley, H. Jeffrey, E. London, H. Sainsbury, I. Nagra, F. Nasir, Ce Dunmore, A. Abraheem, M. Al-Moasseb, R. Girach, C. Brantwood, P. Alexander, J. Bradley-Potts, T. Felton, S. Manna, S. Farnell-Ward, S. Leaver, J. Queiroz, E. Maccacari, D. Dawson, C. Castro Delgado, R. Pepermans Saluzzio, O. Ezeobu, L. Ding, C. Sicat, R. Kanu, The GenOMICC Investigators, GenOMICC Consortium, GenOMICC co-investigators, Central management and laboratory team, Data analysis team, UK Barts Health NHS Trust London, UK Guys and St Thomas’ Hospital London, UK James Cook University Hospital Middlesburgh, UK The Royal Liverpool University Hospital Liverpool, UK King’s College Hospital London, UK Royal Infirmary of Edinburgh Edinburgh, UK John Radcliffe Hospital Oxford, UK Addenbrooke’s Hospital Cambridge, UK Morriston Hospital Swansea, UK Ashford and St Peter’s Hospital Surrey, UK Royal Stoke University Hospital Staffordshire, UK Queen Elizabeth Hospital Birmingham, UK Glasgow Royal Infirmary Glasgow, UK Kingston Hospital Surrey, UK The Tunbridge Wells Hospital and Maidstone Hospital Kent, UK North Middlesex University Hospital NHS Trust London, UK Bradford Royal Infirmary Bradford, UK Blackpool Victoria Hospital Blackpool, UK Countess of Chester Hospital Chester, UK Wythenshawe Hospital Manchester, UK St George’s Hospital London

Original languageEnglish
JournalNature
DOIs
E-pub ahead of print11 Dec 2020

King's Authors

Abstract

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 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 $$\times $$×10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 $$\times $$×10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 $$\times $$×10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 $$\times $$×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.

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