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Whole Genome Sequencing Identifies Multiple Loci for Critical Illness

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Whole Genome Sequencing Identifies Multiple Loci for Critical Illness medRxiv preprint doi: https://doi.org/10.1101/2021.09.02.21262965; this version posted September 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 1 Whole genome sequencing identifies multiple loci for critical 2 illness caused by COVID-19 3 ‡,1 ‡,2,3 2 1 4 Athanasios Kousathanas , Erola Pairo-Castineira , Konrad Rawlik , Alex Stuckey , Christopher 1 1 2,4 5 2 5 A Odhams , Susan Walker , Clark D Russell , Tomas Malinauskas , Jonathan Millar , Katherine 5 2 2 6 7 2 6 S Elliott , Fiona Griffiths , Wilna Oosthuyzen , Kirstie Morrice , Sean Keating , Bo Wang , Daniel 1 3 2 2 3 1 7 Rhodes , Lucija Klaric , Marie Zechner , Nick Parkinson , Andrew D. Bretherick , Afshan Siddiq , 1 1 8 9 10,11 8 Peter Goddard , Sally Donovan , David Maslove , Alistair Nichol , Malcolm G Semple , Tala 1 1 1 1 5 1 9 Zainy , Fiona Maleady-Crowe , Linda Todd , Shahla Salehi , Julian Knight , Greg Elgar , Georgia 1 1 12,13 1 14 10 Chan , Prabhu Arumugam , Tom A Fowler , Augusto Rendon , Manu Shankar-Hari , Charlotte 15 16 17 11 Summers , Paul Elliott , Jian Yang , Yang Wu, GenOMICC Investigators , 23andMe , Covid-19 6 6 18 3 12 Human Genetics Initiative , Angie Fawkes , Lee Murphy , Kathy Rowan , Chris P Ponting , 3 3,19 1,20 *,2 *,1 13 Veronique Vitart , James F Wilson , Richard H Scott , Sara Clohisey , Loukas Moutsianas , *,2 *,12,21 *,2,3,4,7 14 Andy Law , Mark J Caulfield , J. Kenneth Baillie . 15 ‡ - joint first authors 16 * - joint last authors 1 17 Genomics England, London UK 2 18 Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, EH25 9RG, UK 3 19 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, 20 Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK 4 21 Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 22 47 Little France Crescent, Edinburgh, UK 5 23 Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, 24 UK 6 25 Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, EH4 26 2XU, UK 7 27 Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, EH16 5SA, 28 UK 8 29 Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, 30 Kingston, ON, Canada 9 31 Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, 32 Ireland 10 33 NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, 34 Veterinary and Ecological Sciences University of Liverpool, Liverpool, L69 7BE, UK 11 35 Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, 36 Alder Hey Children’s Hospital, Liverpool, UK 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.09.02.21262965; this version posted September 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 12 37 Genomics England, Queen Mary University of London 13 38 Test and Trace, the Health Security Agency, Department of Health and Social Care, Victoria St, 39 London, UK 14 40 Department of Intensive Care Medicine, Guy’s and St. Thomas NHS Foundation Trust, London, 41 UK 15 42 Department of Medicine, University of Cambridge, Cambridge, UK 16 43 Imperial College, London 17 44 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China 18 45 Intensive Care National Audit & Research Centre, London, UK 19 46 Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, 47 Teviot Place, Edinburgh EH8 9AG, UK 20 48 Great Ormond Street Hospital, London UK 21 49 William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, 50 London EC1 6BQ 51 Abstract 52 Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune 53 system. We and others have shown that host genetic variation influences the development of illness 1 2;3;4 54 requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC 55 (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill 56 cases with population controls in order to find underlying disease mechanisms. 57 Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases 58 compared with 48,400 population controls to discover and replicate 22 independent variants that 59 significantly predispose to life-threatening COVID-19. We identify 15 new independent associations 60 with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, 61 PLSCR1 ), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2 ). 62 Using transcriptome-wide association and colocalisation to infer the effect of gene expression 63 on disease severity, we find evidence implicating expression of multiple genes, including reduced 64 expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1 ), in critical 65 disease. 66 We show that comparison between critically-ill cases and population controls is highly efficient for 67 genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. 68 Therapeutic predictions arising from these findings require testing in clinical trials. 2 medRxiv preprint doi: https://doi.org/10.1101/2021.09.02.21262965; this version posted September 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 69 Introduction 70 Critical illness in COVID-19 is both an extreme disease phenotype, and a relatively homogeneous 5 6 71 clinical definition including patients with hypoxaemic respiratory failure with acute lung injury, 7 72 and excluding many patients with non-pulmonary clinical presentations who are known to have 8 73 divergent responses to therapy. In the UK, the critically-ill patient group is younger, less likely 5 74 to have significant comorbidity, and more severely affected than a general hospitalised cohort, 75 characteristics which may amplify observed genetic effects. In addition, since development of critical 8 76 illness is in itself a key clinical endpoint for therapeutic trials, using critical illness as a phenotype 1 77 in genetic studies enables detection of directly therapeutically-relevant genetic effects. 78 Using microarray genotyping in 2,244 cases, we previously reported that critical COVID-19 is 79 associated with genetic variation in the host immune response to viral infection (OAS1, IFNAR2, 1 80 TYK2 ) and the inflammasome regulator DPP9. In collaboration with international groups, we 4 81 recently extended these findings to include a variant near TAC4 (rs77534576). Several variants 82 have been associated with milder phenotypes, such as the need for hospitalisation or management 3 9 83 in the community, including the ABO blood type locus, a pleiotropic inversion in chr17q21.31, 84 and associations in 5 additional loci including the T lymphocyte-associated transcription factor, 4 85 FOXP4. An enrichment of rare loss-of-function variants in candidate interferon signalling genes has 2 10;11 86 been reported, but this has yet to be replicated at genome-wide significance thresholds. 87 We established a partnership between the GenOMICC Study and Genomics England to perform 88 whole genome sequencing (WGS) to improve resolution and deepen fine-mapping of significant 89 signals to enhance the biological insights into critical COVID-19. Here, we present results from a 90 cohort of 7,491 critically-ill patients from 224 intensive care units, compared with 48,400 population 91 controls, describing discovery and validation of 22 gene loci for susceptibility to life-threatening 92 COVID-19. 93 Results 94 Study design 95 Cases were defined by the presence of COVID-19 critical illness in the view of the treating clinician - 96 specifically, the need for continuous cardio-respiratory monitoring. Patients were recruited from 97 224 intensive care units across the UK in the GenOMICC (Genetics Of Mortality In Critical Care) 98 study. As a control population, unrelated participants recruited to the 100,000 Genomes Project 99 were selected, excluding those with a known positive COVID-19 test, as severity information was 100 not available. The 100,000 Genomes Project cohort (100k cohort) is comprised of UK individuals 101 with a broad range of rare diseases or cancer and their family members. We included an additional 102 prospectively-recruited cohort of volunteers (mild cohort) who self-reported testing positive for 103 SARS-CoV-2 infection, and experienced mild or asymptomatic disease. 104 GWAS analysis 105 Whole genome sequencing and subsequent alignment and variant calling was performed for all 106 subjects as described below (Methods). Following quality control procedures, we used a logistic 12 107 mixed model regression, implemented in SAIGE, to perform association analyses with unrelated 3 medRxiv preprint doi: https://doi.org/10.1101/2021.09.02.21262965; this version posted September 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license .
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