Genetic mechanisms of critical illness in Covid-19

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; 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

doi:10.1038/s41586-020-03065-y

Genetic mechanisms of critical illness in Covid-19

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

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

Research output: Contribution to journal › Article › peer-review

1034 Citations (Scopus)

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.

Original language	English
Journal	Nature
DOIs	https://doi.org/10.1038/s41586-020-03065-y
Publication status	E-pub ahead of print - 11 Dec 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41586-020-03065-y

Cite this

Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Fourman, M. H., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., ... St George’s Hospital London, UK. (2020). Genetic mechanisms of critical illness in Covid-19. Nature. Advance online publication. https://doi.org/10.1038/s41586-020-03065-y

@article{e85fdf455a704e61b8f3f60eeb8f7fdb,

title = "Genetic mechanisms of critical illness in Covid-19",

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 \$\$\textbackslash{}times \$\$×10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 \$\$\textbackslash{}times \$\$×10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 \$\$\textbackslash{}times \$\$×10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 \$\$\textbackslash{}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.",

author = "Erola Pairo-Castineira and Sara Clohisey and Lucija Klaric and Bretherick, \{Andrew D.\} and Konrad Rawlik and Dorota Pasko and Susan Walker and Nick Parkinson and Fourman, \{Max Head\} and Russell, \{Clark D.\} and James Furniss and Anne Richmond and Elvina Gountouna and Nicola Wrobel and David Harrison and Bo Wang and Yang Wu and Alison Meynert and Fiona Griffiths and Wilna Oosthuyzen and Athanasios Kousathanas and Loukas Moutsianas and Zhijian Yang and Ranran Zhai and Chenqing Zheng and Graeme Grimes and Rupert Beale and Jonathan Millar and Barbara Shih and Sean Keating and Marie Zechner and Chris Haley and Porteous, \{David J.\} and Caroline Hayward and Jian Yang and Julian Knight and Charlotte Summers and M. Shankar-Hari and Paul Klenerman and Lance Turtle and Antonia Ho and Moore, \{Shona C.\} and Charles Hinds and Peter Horby and Alistair Nichol and David Maslove and Lowell Ling and Danny McAuley and Hugh Montgomery and Timothy Walsh and Alex Pereira and Alessandra Renieri and Johnny Millar and Tim Walsh and Openshaw, \{Peter J.M.\} and Chris Ponting and Jen Meikle and Paul Finernan and Ellie Mcmaster and Andy Law and Baillie, \{J. K.\} and Trevor Paterson and Tony Wackett and Ruth Armstrong and Richard Clark and Audrey Coutts and Lorna Donnelly and Tammy Gilchrist and Katarzyna Hafezi and Louise Macgillivray and Alan Maclean and Sarah McCafferty and Kirstie Morrice and Jane Weaver and Ceilia Boz and Ailsa Golightly and Mari Ward and Hanning Mal and Helen Szoor-McElhinney and Adam Brown and Ross Hendry and Andrew Stenhouse and Louise Cullum and Dawn Law and Sarah Law and Rachel Law and Maaike Swets and Nicky Day and Filip Taneski and Esther Duncan and Nicholas Parkinson and D. Collier and S. Wood and A. Zak and C. Borra and M. Matharu and P. May and Z. Alldis and O. Mitchelmore and R. Bowles and A. Easthorpe and F. Bibi and I. Lancoma-Malcolm and J. Gurasashvili and J. Pheby and J. Shiel and M. Bolton and M. Patel and M. Taylor and O. Zongo and P. Ebano and P. Harding and R. Astin-Chamberlain and Y. Choudhury and A. Cox and D. Kallon and M. Burton and R. Hall and S. Blowes and Z. Prime and J. Biddle and O. Prysyazhna and T. Newman and C. Tierney and J. Kassam and M. Ostermann and S. Campos and A. Bociek and R. Lim and N. Grau and Jones, \{T. O.\} and C. Whitton and M. Marotti and G. Arbane and S. Bonner and K. Hugill and I. Welters and V. Waugh and Roman, \{J. Fernandez\} and Martinez, \{M. Lopez\} and A. Waite and O. Hamilton and S. Mulla and M. McPhail and J. Smith and Baillie, \{J. K.\} and L. Barclay and C. McCulloch and L. McQuillan and J. Singleton and K. Priestley and N. Rea and M. Callaghan and G. Andrew and P. Hutton and A. Bashyal and N. Davidson and C. Summers and P. Polgarova and K. Stroud and N. Pathan and K. Elston and C. Battle and L. Newey and T. Rees and R. Harford and E. Brinkworth and M. Croft and N. Bandla and M. Gellamucho and H. Turner and A. Quinn and I. Hussain and R. Bradley and R. Griffiths and J. Scriven and A. Puxty and S. Cathcart and D. Salutous and K. Duffy and K. Puxty and A. Joseph and R. Herdman-Grant and R. Simms and A. Swain and A. Naranjo and R. Crowe and K. Sollesta and A. Loveridge and D. Baptista and E. Morino and M. Davey and D. Golden and Cuesta, \{J. Moreno\} and A. Haldeos and D. Bakthavatsalam and M. Elhassan and K. Xavier and A. Ganesan and Abdelrazik, \{D. Purohit M.\} and L. Akeroyd and S. Bano and M. Bromley and K. Sellick and L. Gurr and V. Nagarajan and P. Szedlak and J. Cupitt and E. Stoddard and L. Benham and N. Slawson and Z. Bradshaw and M. Caswell and S. Melling and P. Bamford and K. Cawley and H. Jeffrey and E. London and H. Sainsbury and I. Nagra and F. Nasir and Ce Dunmore and A. Abraheem and M. Al-Moasseb and R. Girach and C. Brantwood and P. Alexander and J. Bradley-Potts and T. Felton and S. Manna and S. Farnell-Ward and S. Leaver and J. Queiroz and E. Maccacari and D. Dawson and Delgado, \{C. Castro\} and Saluzzio, \{R. Pepermans\} and O. Ezeobu and L. Ding and C. Sicat and R. Kanu and Investigators, \{The GenOMICC\} and GenOMICC Consortium and GenOMICC co-investigators and team, \{Central management and laboratory\} and team, \{Data analysis\} and \{Barts Health NHS Trust London\}, UK and \{Guys and St Thomas{\textquoteright} Hospital London\}, UK and \{James Cook University Hospital Middlesburgh\}, UK and \{The Royal Liverpool University Hospital Liverpool\}, UK and \{King{\textquoteright}s College Hospital London\}, UK and \{Royal Infirmary of Edinburgh Edinburgh\}, UK and \{John Radcliffe Hospital Oxford\}, UK and \{Addenbrooke{\textquoteright}s Hospital Cambridge\}, UK and \{Morriston Hospital Swansea\}, UK and \{Ashford and St Peter{\textquoteright}s Hospital Surrey\}, UK and \{Royal Stoke University Hospital Staffordshire\}, UK and \{Queen Elizabeth Hospital Birmingham\}, UK and \{Glasgow Royal Infirmary Glasgow\}, UK and \{Kingston Hospital Surrey\}, UK and \{The Tunbridge Wells Hospital and Maidstone Hospital Kent\}, UK and \{North Middlesex University Hospital NHS Trust London\}, UK and \{Bradford Royal Infirmary Bradford\}, UK and \{Blackpool Victoria Hospital Blackpool\}, UK and \{Countess of Chester Hospital Chester\}, UK and \{Wythenshawe Hospital Manchester\}, UK and \{St George{\textquoteright}s Hospital London\}, UK",

year = "2020",

month = dec,

day = "11",

doi = "10.1038/s41586-020-03065-y",

language = "English",

journal = "Nature",

issn = "1476-4687",

publisher = "Nature Research",

}

Pairo-Castineira, E, Clohisey, S, Klaric, L, Bretherick, AD, Rawlik, K, Pasko, D, Walker, S, Parkinson, N, Fourman, MH, Russell, CD, Furniss, J, Richmond, A, Gountouna, E, Wrobel, N, Harrison, D, Wang, B, Wu, Y, Meynert, A, Griffiths, F, Oosthuyzen, W, Kousathanas, A, Moutsianas, L, Yang, Z, Zhai, R, Zheng, C, Grimes, G, Beale, R, Millar, J, Shih, B, Keating, S, Zechner, M, Haley, C, Porteous, DJ, Hayward, C, Yang, J, Knight, J, Summers, C, Shankar-Hari, M, Klenerman, P, Turtle, L, Ho, A, Moore, SC, Hinds, C, Horby, P, Nichol, A, Maslove, D, Ling, L, McAuley, D, Montgomery, H, Walsh, T, Pereira, A, Renieri, A, Millar, J, Walsh, T, Openshaw, PJM, Ponting, C, Meikle, J, Finernan, P, Mcmaster, E, Law, A, Baillie, JK, Paterson, T, Wackett, T, Armstrong, R, Clark, R, Coutts, A, Donnelly, L, Gilchrist, T, Hafezi, K, Macgillivray, L, Maclean, A, McCafferty, S, Morrice, K, Weaver, J, Boz, C, Golightly, A, Ward, M, Mal, H, Szoor-McElhinney, H, Brown, A, Hendry, R, Stenhouse, A, Cullum, L, Law, D, Law, S, Law, R, Swets, M, Day, N, Taneski, F, Duncan, E, Parkinson, N, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthorpe, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, Jones, TO, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Welters, I, Waugh, V, Roman, JF, Martinez, ML, Waite, A, Hamilton, O, Mulla, S, McPhail, M, Smith, J, Baillie, JK, Barclay, L, McCulloch, C, McQuillan, L, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Andrew, G, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Croft, M, Bandla, N, Gellamucho, M, Turner, H, Quinn, A, Hussain, I, Bradley, R, Griffiths, R, Scriven, J, Puxty, A, Cathcart, S, Salutous, D, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Cuesta, JM, Haldeos, A, Bakthavatsalam, D, Elhassan, M, Xavier, K, Ganesan, A, Abdelrazik, DPM, Akeroyd, L, Bano, S, Bromley, M, Sellick, K, Gurr, L, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Slawson, N, Bradshaw, Z, Caswell, M, Melling, S, Bamford, P, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, C, Abraheem, A, Al-Moasseb, M, Girach, R, Brantwood, C, Alexander, P, Bradley-Potts, J, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, Delgado, CC, Saluzzio, RP, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Investigators, TGMICC, Consortium, GMICC, co-investigators, GMICC, team, CMAL, team, DA, 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, UK 2020, 'Genetic mechanisms of critical illness in Covid-19', Nature. https://doi.org/10.1038/s41586-020-03065-y

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, M.

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, Alex

AU - Renieri, Alessandra

AU - Millar, Johnny

AU - Walsh, Tim

AU - Openshaw, Peter J.M.

AU - Ponting, Chris

AU - Meikle, Jen

AU - Finernan, Paul

AU - Mcmaster, Ellie

AU - Law, Andy

AU - Baillie, J. K.

AU - Paterson, Trevor

AU - Wackett, Tony

AU - Armstrong, Ruth

AU - Clark, Richard

AU - Coutts, Audrey

AU - Donnelly, Lorna

AU - Gilchrist, Tammy

AU - Hafezi, Katarzyna

AU - Macgillivray, Louise

AU - Maclean, Alan

AU - McCafferty, Sarah

AU - Morrice, Kirstie

AU - Weaver, Jane

AU - Boz, Ceilia

AU - Golightly, Ailsa

AU - Ward, Mari

AU - Mal, Hanning

AU - Szoor-McElhinney, Helen

AU - Brown, Adam

AU - Hendry, Ross

AU - Stenhouse, Andrew

AU - Cullum, Louise

AU - Law, Dawn

AU - Law, Sarah

AU - Law, Rachel

AU - Swets, Maaike

AU - Day, Nicky

AU - Taneski, Filip

AU - Duncan, Esther

AU - Parkinson, Nicholas

AU - Collier, D.

AU - Wood, S.

AU - Zak, A.

AU - Borra, C.

AU - Matharu, M.

AU - May, P.

AU - Alldis, Z.

AU - Mitchelmore, O.

AU - Bowles, R.

AU - Easthorpe, A.

AU - Bibi, F.

AU - Lancoma-Malcolm, I.

AU - Gurasashvili, J.

AU - Pheby, J.

AU - Shiel, J.

AU - Bolton, M.

AU - Patel, M.

AU - Taylor, M.

AU - Zongo, O.

AU - Ebano, P.

AU - Harding, P.

AU - Astin-Chamberlain, R.

AU - Choudhury, Y.

AU - Cox, A.

AU - Kallon, D.

AU - Burton, M.

AU - Hall, R.

AU - Blowes, S.

AU - Prime, Z.

AU - Biddle, J.

AU - Prysyazhna, O.

AU - Newman, T.

AU - Tierney, C.

AU - Kassam, J.

AU - Ostermann, M.

AU - Campos, S.

AU - Bociek, A.

AU - Lim, R.

AU - Grau, N.

AU - Jones, T. O.

AU - Whitton, C.

AU - Marotti, M.

AU - Arbane, G.

AU - Bonner, S.

AU - Hugill, K.

AU - Welters, I.

AU - Waugh, V.

AU - Roman, J. Fernandez

AU - Martinez, M. Lopez

AU - Waite, A.

AU - Hamilton, O.

AU - Mulla, S.

AU - McPhail, M.

AU - Smith, J.

AU - Baillie, J. K.

AU - Barclay, L.

AU - McCulloch, C.

AU - McQuillan, L.

AU - Singleton, J.

AU - Priestley, K.

AU - Rea, N.

AU - Callaghan, M.

AU - Andrew, G.

AU - Hutton, P.

AU - Bashyal, A.

AU - Davidson, N.

AU - Summers, C.

AU - Polgarova, P.

AU - Stroud, K.

AU - Pathan, N.

AU - Elston, K.

AU - Battle, C.

AU - Newey, L.

AU - Rees, T.

AU - Harford, R.

AU - Brinkworth, E.

AU - Croft, M.

AU - Bandla, N.

AU - Gellamucho, M.

AU - Turner, H.

AU - Quinn, A.

AU - Hussain, I.

AU - Bradley, R.

AU - Griffiths, R.

AU - Scriven, J.

AU - Puxty, A.

AU - Cathcart, S.

AU - Salutous, D.

AU - Duffy, K.

AU - Puxty, K.

AU - Joseph, A.

AU - Herdman-Grant, R.

AU - Simms, R.

AU - Swain, A.

AU - Naranjo, A.

AU - Crowe, R.

AU - Sollesta, K.

AU - Loveridge, A.

AU - Baptista, D.

AU - Morino, E.

AU - Davey, M.

AU - Golden, D.

AU - Cuesta, J. Moreno

AU - Haldeos, A.

AU - Bakthavatsalam, D.

AU - Elhassan, M.

AU - Xavier, K.

AU - Ganesan, A.

AU - Abdelrazik, D. Purohit M.

AU - Akeroyd, L.

AU - Bano, S.

AU - Bromley, M.

AU - Sellick, K.

AU - Gurr, L.

AU - Nagarajan, V.

AU - Szedlak, P.

AU - Cupitt, J.

AU - Stoddard, E.

AU - Benham, L.

AU - Slawson, N.

AU - Bradshaw, Z.

AU - Caswell, M.

AU - Melling, S.

AU - Bamford, P.

AU - Cawley, K.

AU - Jeffrey, H.

AU - London, E.

AU - Sainsbury, H.

AU - Nagra, I.

AU - Nasir, F.

AU - Dunmore, Ce

AU - Abraheem, A.

AU - Al-Moasseb, M.

AU - Girach, R.

AU - Brantwood, C.

AU - Alexander, P.

AU - Bradley-Potts, J.

AU - Felton, T.

AU - Manna, S.

AU - Farnell-Ward, S.

AU - Leaver, S.

AU - Queiroz, J.

AU - Maccacari, E.

AU - Dawson, D.

AU - Delgado, C. Castro

AU - Saluzzio, R. Pepermans

AU - Ezeobu, O.

AU - Ding, L.

AU - Sicat, C.

AU - Kanu, R.

AU - Investigators, The GenOMICC

AU - Consortium, GenOMICC

AU - co-investigators, GenOMICC

AU - team, Central management and laboratory

AU - team, Data analysis

AU - Barts Health NHS Trust London, UK

AU - Guys and St Thomas’ Hospital London, UK

AU - James Cook University Hospital Middlesburgh, UK

AU - The Royal Liverpool University Hospital Liverpool, UK

AU - King’s College Hospital London, UK

AU - Royal Infirmary of Edinburgh Edinburgh, UK

AU - John Radcliffe Hospital Oxford, UK

AU - Addenbrooke’s Hospital Cambridge, UK

AU - Morriston Hospital Swansea, UK

AU - Ashford and St Peter’s Hospital Surrey, UK

AU - Royal Stoke University Hospital Staffordshire, UK

AU - Queen Elizabeth Hospital Birmingham, UK

AU - Glasgow Royal Infirmary Glasgow, UK

AU - Kingston Hospital Surrey, UK

AU - The Tunbridge Wells Hospital and Maidstone Hospital Kent, UK

AU - North Middlesex University Hospital NHS Trust London, UK

AU - Bradford Royal Infirmary Bradford, UK

AU - Blackpool Victoria Hospital Blackpool, UK

AU - Countess of Chester Hospital Chester, UK

AU - Wythenshawe Hospital Manchester, UK

AU - St George’s Hospital London, UK

PY - 2020/12/11

Y1 - 2020/12/11

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-020-03065-y

DO - 10.1038/s41586-020-03065-y

M3 - Article

SN - 1476-4687

JO - Nature

JF - Nature

ER -

Genetic mechanisms of critical illness in Covid-19

Abstract

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