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- Johnny Millar, Alistair Nichol, Tim Walsh, Manu Shankar-Hari, Chris Ponting, Jen Meikle, Paul Finernan, Ellie Mcmaster, Andy Law, J. Kenneth 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. Easthope, 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. Shankar-Hari, M. Ostermann, S. Campos, A. Bociek, R. Lim, N. Grau, T. O. Jones, C. Whitton, M. Marotti, G. Arbane, S. Bonner, K. Hugill, J. Reid, I. Welters, V. Waugh, K. Williams, D. Shaw, J. Fernandez Roman, M. Lopez Martinez, E. Johnson, A. Waite, B. Johnston, D. Hamilton, S. Mulla, M. McPhail, J. Smith, J. K. Baillie, L. Barclay, D. Hope, C. McCulloch, L. McQuillan, S. Clark, J. Singleton, K. Priestley, N. Rea, M. Callaghan, R. Campbell, G. Andrew, L. Marshall, S. McKechnie, P. Hutton, A. Bashyal, N. Davidson, C. Summers, P. Polgarova, K. Stroud, N. Pathan, K. Elston, S. Agrawal, C. Battle, L. Newey, T. Rees, R. Harford, E. Brinkworth, M. Williams, C. Murphy, I. White, M. Croft, N. Bandla, M. Gellamucho, J. Tomlinson, H. Turner, M. Davies, A. Quinn, I. Hussain, C. Thompson, H. Parker, R. Bradley, R. Griffiths, J. Scriven, A. Nilsson, M. Bates, J. Dasgin, J. Gill, A. Puxty, S. Cathcart, D. Salutous, L. Turner, 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. Jones, J. Moreno Cuesta, A. Haldeos, D. Bakthavatsalam, R. Vincent, M. Elhassan, K. Xavier, A. Ganesan, D. Purohit, M. Abdelrazik, J. Morgan, L. Akeroyd, S. Bano, T. Lawton, D. Warren, M. Bromley, K. Sellick, L. Gurr, B. Wilkinson, V. Nagarajan, P. Szedlak, J. Cupitt, E. Stoddard, L. Benham, S. Preston, S. Laha, N. Slawson, Z. Bradshaw, J. Brown, M. Caswell, S. Melling, P. Bamford, M. Faulkner, K. Cawley, H. Jeffrey, E. London, H. Sainsbury, I. Nagra, F. Nasir, C. Dunmore, R. Jones, A. Abraheem, M. Al-Moasseb, R. Girach, G. Padden, J. Egan, C. Brantwood, P. Alexander, J. Bradley-Potts, S. Allen, 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, G. Durrant, J. Texeira, A. Harrison, T. Samakomva, J. Scriven, H. Willis, B. Hopkins, L. Thrasyvoulou, M. Jackson, A. Zaki, C. Tibke, S. Bennett, W. Woodyatt, A. Kent, E. Goodwin, C. Brandwood, R. Clark, L. Smith, K. Rooney, N. Thomson, N. Rodden, E. Hughes, D. McGlynn, C. Clark, P. Clark, L. Abel, R. Sundaram, L. Gemmell, M. Brett, J. Hornsby, P. MacGoey, R. Price, B. Digby, P. O'Neil, P. McConnell, P. Henderson, S. Henderson, M. Sim, S. Kennedy-Hay, C. McParland, L. Rooney, N. Baxter, D. Pogson, S. Rose, Z. Daly, L. Brimfield, M. K. Phull, M. Hussain, T. Pogreban, L. Rosaroso, E. Salciute, L. Grauslyte, D. Brealey, E. Raith, N. MacCallum, G. Bercades, I. Hass, D. Smyth, A. Reyes, G. Martir, I. D. Clement, K. Webster, C. Hays, A. Gulati, L. Hodgson, M. Margarson, R. Gomez, Y. Baird, Y. Thirlwall, L. Folkes, A. Butler, E. Meadows, S. Moore, D. Raynard, H. Fox, L. Riddles, K. King, S. Kimber, G. Hobden, A. McCarthy, V. Cannons, I. Balagosa, I. Chadbourn, A. Gardner, D. Horner, D. McLaughlanv, B. Charles, N. Proudfoot, T. Marsden, L. McMorrow, B. Blackledge, J. Pendlebury, A. Harvey, E. Apetri, C. 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Martin, E. Bevan, C. Wrey Brown, D. Trodd, K. English, G. Bell, L. Wilcox, A. Katary, S. Gopal, V. Lake, N. Harris, S. Metherell, E. Radford, J. Scriven, F. Moore, H. Bancroft, J. Daglish, M. Sangombe, M. Carmody, J. Rhodes, M. Bellamy, A. Garg, A. Kuravi, E. Virgilio, P. Ranga, J. Butler, L. Botfield, C. Dexter, J. Fletcher, P. Shanmugasundaram, G. Hambrook, I. Burn, K. Manso, D. Thornton, J. Tebbutt, R. Penn, J. Hulme, S. Hussain, Z. Maqsood, S. Joseph, J. Colley, A. Hayes, C. Ahmed, R. Haq, S. Clamp, R. Kumar, M. Purewal, B. Baines, M. Frise, N. Jacques, H. Coles, J. Caterson, S. Gurung Rai, M. Brunton, E. Tilney, L. Keating, A. Walden, D. Antcliffe, S. Brett, A. Gordon, M. Templeton, R. Rojo, D. Banach, S. Sousa Arias, Z. Fernandez, P. Coghlan, D. Williams, C. Jardine, J. Bewley, K. Sweet, L. Grimmer, R. Johnson, Z. Garland, B. Gumbrill, C. Phillips, L. Ortiz-Ruiz de Gordoa, E. Peasgood, A. Tridente, K. Shuker, S. Greer, C. Lynch, C. Pothecary, L. Roche, B. Deacon, K. Turner, J. 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T-Michael, M. Bruce, K. Connolly, K. Smith, R. Partridge, D. Griffin, M. Mupudzi, N. Muchenje, D. Martin, H. Filipe, C. Eastgate, C. Jackson, A. Gratrix, L. Foster, V. Martinson, E. Stones, Caroline Abernathy, P. Parkinson, A. Reed, C. Prendergast, P. Rogers, M. Woodruff, R. Shokkar, S. Kaul, A. Barron, C. Collins, S. Beavis, A. Whileman, K. Dale, J. Hawes, K. Pritchard, R. Gascoyne, L. Stevenson, R. Jha, L. Lim, V. Krishnamurthy, R. Parker, I. Turner-Bone, L. Wilding, A. Reddy, S. Whiteley, E. Wilby, C. Howcroft, A. Aspinwall, S. Charlton, B. Ogg, D. Menzies, R. Pugh, E. Allan, R. Lean, F. Davies, J. Easton, X. Qiu, S. Kumar, K. Darlington, G. Houston, P. O'Brien, T. Geary, J. Allan, A. Meikle, G. Hughes, M. Balasubramaniam, S. Latham, E. McKenna, R. Flanagan, S. Sathe, E. Davies, L. Roche, M. Chablani, A. Kirkby, K. Netherton, S. Archer, B. Yates, C. Ashbrook-Raby, S. Cole, M. Casey, L. Cabrelli, S. Chapman, A. Hutcheon, C. Whyte, C. Almaden-Boyle, N. Pattison, C. Cruz, A. 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Fernandes, I. Ali Mohamed Ali, H. Rangarajan, V. Sarathy, S. Selvanayagam, D. Vedage, M. White, M. Smith, N. Truman, S. Chukkambotla, S. Keith, J. Cockerill-Taylor, J. Ryan-Smith, R. Bolton, P. Springle, J. Dykes, J. Thomas, M. Khan, M. T. Hijazi, E. Massey, G. Croston, H. Reschreiter, J. Camsooksai, S. Patch, S. Jenkins, C. Humphrey, B. Wadams, M. Msiska, O. Adanini, B. Attwood, P. Parsons, K. Tatham, S. Jhanji, E. Black, A. Dela Rosa, R. Howle, B. Thomas, T. Bemand, R. Raobaikady, R. Saha, N. Staines, A. Daniel, J. Finn, J. Hutter, P. Doble, C. Shovelton, C. Pawley, T. Kannan, M. Hill, E. Combes, S. Monnery, T. Joefield, M. Popescu, M. Thankachen, M. Oblak, J. Little, S. McIvor, A. Brady, H. Whittle, H. Prady, R. Chan, A. Ahmed, A. Morris, C. Gibson, E. Gordon, S. Keenan, H. Quinn, S. Benyon, S. Marriott, L. Zitter, L. Park, K. Baines, M. Lyons, M. Holland, N. Keenan, M. Young, S. Garrioch, J. Dawson, M. Tolson, B. Scholefield, R. Bi, N. Richardson, N. Schumacher, T. Cosier, G. 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Thrush, A. Durie, K. Austin, K. Archer, P. Anderson, C. Vigurs, C. Thorpe, A. Thomas, E. Knights, N. Boyle, A. Price, A. Kubisz-Pudelko, D. Wood, A. Lewis, S. Board, L. Pippard, J. Perry, K. Beesley, A. Rattray, M. Taylor, E. Lee, L. Lennon, K. Douglas, D. Bell, R. Boyle, L. Glass, M. Nauman Akhtar, K. Dent, D. Potoczna, S. Pearson, E. Horsley, S. Spencer, C. Phillips, D. Mullan, D. Skinner, J. Gaylard, L. Ortiz-Ruiz de Gordoa, R. Barber, C. Hewitt, A. Hilldrith, S. Shepardson, M. Wills, K. Jackson-Lawrence, A. Gupta, A. Easthope, E. Timlick, C. Gorman, I. Otahal, A. Gales, S. Coetzee, C. Sell, M. Raj, M. Peiu, V. Parris, S. Quaid, E. Watson, K. Elliott, J. Mallinson, B. Chandler, A. Turnbull, A. Quinn, C. Finch, C. Holl, J. Cooper, A. Evans, W. Khaliq, A. Collins, E. Treus Gude, N. Love, L. van Koutrik, J. Hunt, D. Kaye, E. Fisher, A. Brayne, V. Tuckey, P. Jackson, J. Parkin, D. Brealey, E. Raith, A. Tariq, H. Houlden, A. Tucci, J. Hardy, E. Moncur, J. Highgate, A. Cowley, A. Mitra, R. Stead, T. Behan, C. Burnett, M. Newton, E. Heeney, R. Pollard, J. Hatton, A. Patel, V. Kasipandian, S. Allibone, R. M. Genetu, I. Otahal, L. O'Brien, Z. Omar, E. Perkins, K. Davies, D. Tetla, C. Pothecary, B. Deacon, B. Shelley, V. Irvine, S. Williams, P. Williams, J. Birch, J. Goodsell, R. Tutton, L. Bough, B. Winter-Goodwin, R. Kitson, J. Pinnell, A. Wilson, T. Nortcliffe, T. Wood, M. Home, K. Holdroyd, M. Robinson, K. Hanson, R. Shaw, J. Greig, M. Brady, A. Haigh, L. Matupe, M. Usher, S. Mellor, S. Dale, L. Gledhill, L. Shaw, G. Turner, D. Kelly, B. Anwar, H. Riley, H. Sturgeon, A. Ali, L. Thomis, D. Melia, A. Dance, S. Humphreys, I. Frost, V. Gopal, J. Godden, A. Holden, S. Swann, T. Smith, M. Clapham, U. Poultney, R. Harper, P. Rice, W. Khaliq, R. Reece-Anthony, B. Gurung, S. Moultrie, M. Odam, A. Mayer, A. Bellini, A. Pickard, J. Bryant, N. Roe, J. Sowter, D. Butcher, K. Lang, J. Taylor, P. Barry, M. Hobrok, H. Tench, R. Wolf-Roberts, H. McGuinness, R. Loosley, D. Hawcutt, L. Rad, L. O'Malley, P. Saunderson, G. Seddon, T. Anderson, N. Rogers, J. Ruddy, M. Harkins, M. Taylor, C. Beith, A. McAlpine, L. Ferguson, P. Grant, S. MacFadyen, M. McLaughlin, T. Baird, S. Rundell, L. Glass, B. Welsh, R. Hamill, F. Fisher, T. Smith, J. Gregory, A. Brown, A. Campbell, S. Smuts, J. Kenneth Baillie, Gail Carson, Beatrice Alex, Benjamin Bach, Wendy S. Barclay, Debby Bogaert, Meera Chand, Graham S. Cooke, Annemarie B. Docherty, Jake Dunning, Ana da Silva Filipe, Tom Fletcher, Christoper A. Green, Ewen M. Harrison, Julian A. Hiscox, Antonia Ying Wai Ho, Peter W. Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Wei Shen Lim, Alexander J. Mentzer, Laura Merson, Alison M. Meynert, Mahdad Noursadeghi, Shona C. Moore, Massimo Palmarini, William A. Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L. Robertson, Vanessa Sancho-Shimizu, Janet T. Scott, Thushan de Silva, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Richard S. Tedder, Emma C. Thomson, A. A. Roger Thompson, Ryan S. Thwaites, Lance C. W. Turtle, Maria Zambon, Hayley Hardwick, Chloe Donohue, Ruth Lyons, Lisa Norman, Riinu Pius, Thomas M. Drake, Cameron J. Fairfield, Stephen R. Knight, Kenneth A. Mclean, Derek Murphy, Catherine A. Shaw, Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Gary Leeming, Murray Wham, William Greenhalf, Victoria Shaw, Sara McDonald, Seán Keating, Andrea Ganna, Patrick Sulem, David A. van Heel, Mattia Cordioli, Gardar Sveinbjornsson, Mari E. K. Niemi, Francesca Mari, Sergio Daga, Margherita Baldassarri, Elisa Benetti, Simone Furini, Chiara Fallerini, Francesca Fava, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Anna Maria Pinto, Elisa Frullanti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Francesca Montagnani, Laura Di Sarno, Andrea Tommasi, Maria Palmieri, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Giacomo Zanelli, Elena Bargagli, Laura Bergantini, Miriana D'Alessandro, Paolo Cameli, David Bennet, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Maurizio Spagnesi, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Massimo Vaghi, Antonella D'Arminio Monforte, Esther Merlini, Mario U. Mondelli, Stefania Mantovani, Serena Ludovisi, Massimo Girardis, Sophie Venturelli, Marco Sita, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Maria Eugenia Quiros-Roldan, Paola Magro, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Stefano Baratti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Giancarlo Bosio, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Nicola Picchiotti, Marco Gori, Chiara Gabbi, Maurizio Sanarico, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella
- Publish date:
- 11 December 2020
- Journal:
- Nature
- PubMed ID:
- 33307546
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.