Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

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Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care[1][1] or hospitalisation[2][2];[3][3];[4][4] following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling ( IL10RB, PLSCR1 ), leucocyte differentiation ( BCL11A ), and blood type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase ( ATP11A ), and increased mucin expression ( MUC1 ), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials. ### Competing Interest Statement Genomics England Ltd is a wholly owned Department of Health and Social Care company created in 2013 to work with the NHS to introduce advanced genomic technologies and analytics into healthcare. All Genomics England affiliated authors are, or were, salaried by Genomics England during this programme. ### Clinical Protocols ### Funding Statement GenOMICC was funded by the Department of Health and Social Care (DHSC), LifeArc, the Medical Research Council, UKRI, Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome-Beit Prize award to J. K. Baillie (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). Whole-genome sequencing was performed by Illumina at the NHS Genomic Sequencing Centre in partnership and was overseen by Genomics England. We would like to thank all at Genomics England who have contributed to the supporting the processing of the sequencing data. We thank DHSC, the Medical Research Council, UKRI, LifeArc, Genomics England Ltd and Illumina Inc for funding sequencing. 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. We are grateful for the support from Professor Dame Sue Hill and the team in NHS England and the 13 Genomic Medicine Centres that successfully delivered the 100,000 Genomes Project which provide the control sequences for this study. We thank the participants of the 100,000 Genomes Project who made this study possible and the Genomics England Participant Panel for their strategic advice, involvement and engagement. We acknowledge NHS Digital, Public Health England and the Intensive Care National Audit and Research Consortium who provided life course longitudinal clinical data on the participants. This work forms part of the portfolio of research of the NIHR Biomedical Research Centre at Barts. Mark Caulfield is an NIHR Senior Investigator. This study owes a great deal to the National Institute of Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GenOMICC was both approved by the appropriate research ethics committees (Scotland, 15/SS/0110; England, Wales and Northern Ireland, 19/WM/0247). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics will be shared openly with international collaborators to accelerate discovery. Data can be obtained from https://genomicc.org/data/ Individual-level data will be available in the UK Outbreak Analysis Platform at the University of Edinburgh and through the Genomics England research environment. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4
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Athanasios Kousathanas, Genomics England, Http, Erola Pairo-Castineira, Roslin Institute, University Of Edinburgh, Easter Bush, Mrc Human Genetics Unit, Institute Of Genetics, Molecular Medicine
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