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; Manu 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; Alexandre C. Pereira; Alessandra Renieri; The GenOMICC Investigators; The ISARIC4C Investigators; The COVID-19 Human Genetics Initiative; 23andMe Investigators; BRACOVID Investigators; Gen-COVID Investigators; Xia Shen; Chris P. Ponting; Angie Fawkes; Albert Tenesa; Mark Caulfield; Richard Scott; Kathy Rowan; Lee Murphy; Peter J.M. Openshaw; Malcolm G. Semple; Andrew Law; Veronique Vitart; James F. Wilson; J. Kenneth Baillie

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 OosthuyzenAthanasios 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, Manu 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, Alexandre C. Pereira, Alessandra Renieri, The GenOMICC Investigators, The ISARIC4C Investigators, The COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Xia Shen, Chris P. Ponting, Angie Fawkes, Albert Tenesa, Mark Caulfield, Richard Scott, Kathy Rowan, Lee Murphy, Peter J.M. Openshaw, Malcolm G. Semple, Andrew Law, Veronique Vitart, James F. Wilson, J. Kenneth Baillie

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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.

Original language	English
Pages (from-to)	92-98
Number of pages	7
Journal	Nature
Volume	591
Issue number	7848
DOIs	https://doi.org/10.1038/s41586-020-03065-y
Publication status	Published - 4 Mar 2021

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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., ... Baillie, J. K. (2021). Genetic mechanisms of critical illness in COVID-19. Nature, 591(7848), 92-98. https://doi.org/10.1038/s41586-020-03065-y

@article{8ae2a5ced93f4f8986704c1e80882024,

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

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.",

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 Manu 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 Pereira, {Alexandre C.} and Alessandra Renieri and {The GenOMICC Investigators} and {The ISARIC4C Investigators} and {The COVID-19 Human Genetics Initiative} and {23andMe Investigators} and {BRACOVID Investigators} and {Gen-COVID Investigators} and Xia Shen and Ponting, {Chris P.} and Angie Fawkes and Albert Tenesa and Mark Caulfield and Richard Scott and Kathy Rowan and Lee Murphy and Openshaw, {Peter J.M.} and Semple, {Malcolm G.} and Andrew Law and Veronique Vitart and Wilson, {James F.} and Baillie, {J. Kenneth}",

year = "2021",

month = mar,

day = "4",

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

language = "English",

volume = "591",

pages = "92--98",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7848",

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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, AC, Renieri, A, The GenOMICC Investigators, The ISARIC4C Investigators, The COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Shen, X, Ponting, CP, Fawkes, A, Tenesa, A, Caulfield, M, Scott, R, Rowan, K, Murphy, L, Openshaw, PJM, Semple, MG, Law, A, Vitart, V, Wilson, JF & Baillie, JK 2021, 'Genetic mechanisms of critical illness in COVID-19', Nature, vol. 591, no. 7848, pp. 92-98. 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, 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 - The GenOMICC Investigators

AU - The ISARIC4C Investigators

AU - The 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.

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U2 - 10.1038/s41586-020-03065-y

DO - 10.1038/s41586-020-03065-y

M3 - Article

C2 - 33307546

AN - SCOPUS:85102602000

VL - 591

SP - 92

EP - 98

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7848

ER -

Genetic mechanisms of critical illness in COVID-19

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