Genetic mechanisms of critical illness in COVID-19

GEN-COVID Contributors; The GenOMICC Investigators; GenOMICC Consortium; GenOMICC co-investigators; Central management and laboratory team; Data analysis team; The ISARIC4C Investigators; ISARIC4C Consortium; ISARIC co-investigators; Project management team; Data architecture team; Data analysis and management team; The COVID-19 Human Genetics Initiative; HGI Consortium (COVID-19 Host Genetics Initiative); 23andMe Investigators; The 23andMe COVID-19 Team; BRACOVID Investigators; Gen-COVID Investigators

doi:10.1038/s41586-020-03065-y

Genetic mechanisms of critical illness in COVID-19

GEN-COVID Contributors, The GenOMICC Investigators, GenOMICC Consortium, GenOMICC co-investigators, Central management and laboratory team, Data analysis team, The ISARIC4C Investigators, ISARIC4C Consortium, ISARIC co-investigators, Project management team, Data architecture team, Data analysis and management team, The COVID-19 Human Genetics Initiative, HGI Consortium (COVID-19 Host Genetics Initiative), 23andMe Investigators, The 23andMe COVID-19 Team, BRACOVID Investigators, Gen-COVID Investigators

Medicine, Cardiology Division

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

918 Scopus citations

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 (US)
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
State	Published - Mar 4 2021

Funding

Acknowledgements We thank the patients and their loved ones who volunteered to contribute to this study at one of the most difficult times in their lives, and the research staff in every intensive care unit who recruited patients at personal risk during the most extreme conditions that we have ever witnessed in UK hospitals; R. Coll for advice on the interpretation of these results; J. Zheng for sharing the harmonized GWAS summary statistics used in LD-Hub; and P. McLaren for substantive improvements to the manuscript and analysis. GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome-Beit Prize award to J.K.B. (Wellcome Trust 103258/Z/13/A) and a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275). WGS was done in partnership with Genomics England and was funded by UK Department of Health and Social Care, UKRI and LifeArc. ISARIC4C is supported by grants from the Medical Research Council (grant MC_PC_19059), the National Institute for Health Research (NIHR) (award CO-CIN-01) and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Wellcome Trust and Department for International Development (215091/Z/18/Z), and the Bill and Melinda Gates Foundation (OPP1209135), and Liverpool Experimental Cancer Medicine Centre (grant reference: C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (IS-BRC-1215-20013), EU Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) (FP7 project 6025250 and NIHR Clinical Research Network provide infrastructure support for this research. P.J.M.O. is supported by a NIHR Senior Investigator Award (award 201385). H.M. was supported by the NIHR BRC at University College London Hospitals. The Health Research Board of Ireland (Clinical Trial Network Award 2014-12) funded the collection of samples in Ireland. This research has been conducted using the UK Biobank Resource under project 788. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the Generation Scotland: Scottish Family Health Study (GS:SFHS) samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award STratifying Resilience and Depression Longitudinally (STRADL) reference 104036/Z/14/Z). Genomics England and the 100,000 Genomes Project was funded by the National Institute for Health Research, the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care and NHS England. M. Caulfield is an NIHR Senior Investigator. This work is part of the portfolio of translational research at the NIHR Biomedical Research Centre at Barts and Cambridge. Research performed at the Human Genetics Unit was funded by the MRC (MC_UU_00007/10, MC_UU_00007/15). L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). A.D.B. acknowledges funding from the Wellcome Trust PhD training fellowship for clinicians (204979/Z/16/Z), and the Edinburgh Clinical Academic Track (ECAT) programme. We acknowledge support from the MRC Human Genetics Unit programme grant \u2018Quantitative traits in health and disease\u2019 (U. MC_UU_00007/10). A.T. acknowledges funding from MRC research grant MR/P015514/1, and HDR-UK award HDR-9004 and HDR-9003. We acknowledge the National Institute of Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist Office (Scotland), who facilitated recruitment into research studies in NHS hospitals, and the global ISARIC and InFACT consortia. The views expressed are those of the authors and not necessarily those of the DHSC, DID, NIHR, MRC, Wellcome Trust or PHE. The views expressed here are purely those of the authors and may not in any circumstances be regarded as stating an official position of the European Commission.

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10.1038/s41586-020-03065-y

Cite this

GEN-COVID Contributors, The GenOMICC Investigators, GenOMICC Consortium, GenOMICC co-investigators, Central management and laboratory team, Data analysis team, The ISARIC4C Investigators, ISARIC4C Consortium, ISARIC co-investigators, Project management team, Data architecture team, Data analysis and management team, The COVID-19 Human Genetics Initiative, HGI Consortium (COVID-19 Host Genetics Initiative), 23andMe Investigators, The 23andMe COVID-19 Team, BRACOVID Investigators, & Gen-COVID Investigators (2021). Genetic mechanisms of critical illness in COVID-19. Nature, 591(7848), 92-98. https://doi.org/10.1038/s41586-020-03065-y

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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 = "{GEN-COVID Contributors} and {The GenOMICC Investigators} and {GenOMICC Consortium} and {GenOMICC co-investigators} and {Central management and laboratory team} and {Data analysis team} and {The ISARIC4C Investigators} and {ISARIC4C Consortium} and {ISARIC co-investigators} and {Project management team} and {Data architecture team} and {Data analysis and management team} and {The COVID-19 Human Genetics Initiative} and {HGI Consortium (COVID-19 Host Genetics Initiative)} and {23andMe Investigators} and {The 23andMe COVID-19 Team} and {BRACOVID Investigators} and {Gen-COVID Investigators} and 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 M. Smith",

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

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GEN-COVID Contributors, The GenOMICC Investigators, GenOMICC Consortium, GenOMICC co-investigators, Central management and laboratory team, Data analysis team, The ISARIC4C Investigators, ISARIC4C Consortium, ISARIC co-investigators, Project management team, Data architecture team, Data analysis and management team, The COVID-19 Human Genetics Initiative, HGI Consortium (COVID-19 Host Genetics Initiative), 23andMe Investigators, The 23andMe COVID-19 Team, BRACOVID Investigators & Gen-COVID Investigators 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

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AU - The ISARIC4C Investigators

AU - ISARIC4C Consortium

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AU - Data architecture team

AU - Data analysis and management team

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AU - Clohisey, Sara

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AU - Wu, Yang

AU - Meynert, Alison

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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

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AU - Porteous, David J.

AU - Hayward, Caroline

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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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Genetic mechanisms of critical illness in COVID-19

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