[Paper] Translation of a Paper on COVID-19 and Genetics #1

Genetic Mechanisms of Severe COVID-19
Results
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Genetic Mechanisms of Severe COVID-19

Received: September 27, 2020
Accepted: November 30, 2020
Accelerated article preview published
Online publication date: December 11, 2020
To cite this article: Pairo-Castineira, E. et al.
Genetic mechanisms of severe COVID-19.
Nature https://doi.org/10.1038/

s41586-020-03065-y (2020).

Erola Pairo-Castineira^1,2,325, Sara Clohisey^1,325, Lucija Klaric^2,325, Andrew D. Bretherick^2,325, Konrad Rawlik^1,325, Dorota Pasko³, Susan Walker³, Nick Parkinson¹, Max Head Fourman¹, Clark D. Russell^1,4, James Furniss¹, Anne Richmond², Elvina Gountouna⁵, Nicola Wrobel⁶, David Harrison⁷, Bo Wang¹, Yang Wu⁸, Alison Meynert², Fiona Griffiths¹, Wilna Oosthuyzen¹, Athanasios Kousathanas³, Loukas Moutsianas³, Zhijian Yang⁹, Ranran Zhai⁹, Chenqing Zheng⁹, Graeme Grimes², Rupert Beale¹⁰, Jonathan Millar¹, Barbara Shih¹, Sean Keating¹¹, Marie Zechner¹, Chris Haley¹, David J. Porteous5, Caroline Hayward^2,5, Jian Yang^12,13, Julian Knight¹⁴, Charlotte Summers¹⁵, Manu Shankar-Hari^16,17, Paul Klenerman¹⁴, Lance Turtle¹⁸, Antonia Ho¹⁹, Shona C. Moore¹⁸, Charles Hinds²⁰, Peter Horby²¹, Alistair Nichol^22,23,24, David Maslove²⁵, Lowell Ling²⁶, Danny McAuley^27,28, Hugh Montgomery²⁹, Timothy Walsh¹¹, Alex Pereira³⁰, Alessandra Renieri^31,32, The GenOMICC Investigators^*, The ISARIC4C Investigators^*, The COVID-19 Human Genetics Initiative^*, 23andMe Investigators^*, BRACOVID Investigators^*, Gen-COVID Investigators^*, Xia Shen^9,33,34, Chris P. Ponting², Angie Fawkesv⁶, Albert Tenesa^1,2,33, Mark Caulfield^3,20, Richard Scott^3,35, Kathy Rowan⁷, Lee Murphy⁶, Peter J. M. Openshaw^36,37, Malcolm G. Semple^18,38, Andrew Law¹, Veronique Vitart², James F. Wilson^2,33 & J. Kenneth Baillie^{1,2,11 ✉}

Severe illness caused by Covid-19 involves host-mediated lung inflammation, which increases mortality rates. Host genetic variations associated with severe disease may identify targets for therapeutic development. Here, we report the results of a 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 at chr12q24.13 (rs10735079, p = 1.65×10-8) within a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), chr19p13.2 (rs2109069, p = 2.3×10-12) near TYK2, chr19p13.3 (rs2109069, p = 3.98×10-12) within DPP9, and chr21q22.1 (rs2236757, p = 4.99×10-8) within the interferon receptor gene IFNAR2. These associations identify potential targets for repurposing approved drugs. Using Mendelian randomization, we found evidence supporting a causal relationship between low expression of IFNAR2 and high expression of TYK2 with 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 strong genetic signals related to key host antiviral defense mechanisms and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted therapy with existing drugs. Large-scale randomized clinical trials are essential before any changes in clinical practice.

Severe illness from Covid-19 is partly caused by inflammatory damage affecting the lungs and pulmonary vasculature. There are at least two distinct biological components to the risk of death: susceptibility to viral infection and propensity to develop harmful lung inflammation. Susceptibility to life-threatening infections and immune-mediated diseases is highly heritable. Specifically, susceptibility to respiratory viruses such as influenza is known to be heritable and associated with specific genetic variants. In Covid-19, a single locus at 3p21.31 has been repeatedly associated with hospitalization. As with other viral diseases, loss-of-function variants affecting essential immune processes, such as TLR7 and associated genes, have been identified in young people with severe disease. Genome-wide studies have the potential to uncover entirely novel molecular mechanisms of severe disease in Covid-19, which may provide therapeutic targets to modulate the host immune response and improve survival.

There is now strong evidence that severe illness caused by Covid-19 is qualitatively different from mild or moderate disease, even among hospitalized patients. Patterns of symptoms vary, and there are distinct disease phenotypes with markedly different responses to immunosuppressive therapy. In patients without respiratory failure, treatment may cause harm, whereas in patients with severe respiratory failure, corticosteroid use yields substantial benefits. Based on this, we consider that patients with severe Covid-19 respiratory failure have a distinct pathophysiology. In the UK, patients admitted to intensive care for life-threatening illness are relatively homogeneous, typically presenting with severe hypoxic respiratory failure. These patients' active disease processes respond markedly to corticosteroid therapy and are characterized by lung inflammation, including diffuse alveolar damage, pulmonary macrophage/monocyte influx, mononuclear cell pulmonary vasculitis, and microthrombosis. Host-directed therapies have long been desired for treating severe disease caused by respiratory viruses. Identification of loci associated with susceptibility to Covid-19 may lead to specific targets for drug repurposing or development.

The GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) study has been recruiting patients with severe syndromes such as influenza, sepsis, and emerging infections for five years. To better understand host mechanisms leading to life-threatening Covid-19, we conducted a genome-wide association study comparing critically ill Covid-19 patients with controls from a UK population genetics study.

Results

Severe cases were recruited through the GenOMICC study in 208 UK intensive care units, and hospitalized cases were recruited through the ISARIC Coronavirus Clinical Characterization Consortium (4C) study. DNA was extracted from high-quality whole blood and array-based genome-wide genotyping obtained from 2734 unique individuals (Materials and Methods). Genetic ancestry was inferred using principal component analysis and individuals from the 1000 Genomes Project as the population reference (Materials and Methods). After quality control and matching to ancestry groups, 2244 individuals were included in the GWAS analysis. The clinical and demographic characteristics of these cases are shown in Extended Data Table 1. Additional clinical details for a subset of 1069 cases with available supplementary data are shown in Supplementary Figures 7-13 and Supplementary Table 2. The cases were critically representative of the UK population with severe illness. In this multi-ancestry cohort, imputation was performed using the TOPMed reference panel.

Ancestry-matched controls were selected from the large population-based cohort UK Biobank (five controls for each case). Controls known to have tested positive for Covid-19 were excluded. The inevitable presence of individuals in the control group who might exhibit severe illness phenotypes if exposed to SARS-CoV-2 is expected to bias associations towards the null. GWAS was performed separately for each ancestry group using logistic regression in PLINK, adjusting for age, sex, decile of postal code deprivation, and ancestry principal components. In addition to several standard filters to minimize spurious associations (Materials and Methods), a subset of 1613 cases underwent whole-genome sequencing to filter out poorly called or imputed variants. Therefore, of the 4,469,187 imputed variants that passed other quality control filters after GWAS, 83,937 were filtered out. There was a high level of residual inflation in the South Asian and East Asian ancestry groups, making results from these subgroups unreliable (Extended Data Fig. 1, Supplementary Fig. 4). The largest ancestry group included 1676 individuals of European ancestry (EUR), which was used for the primary analysis presented below.

GWAS Results

In the primary analysis (GenOMICC European cases vs. UK Biobank controls), 15 independent association signals were genome-wide significant at p<5×10-8 after linkage disequilibrium-based clumping (Supplementary Fig. 1). Of these, eight were successfully validated in GWAS using two independent population genetic studies (100,000 Genomes and Generation Scotland) as controls (Table 1), leading to their replication. The sex-specific GWAS in this group did not reveal any sex-specific associations (Supplementary Table 1). No additional associations were identified in the trans-ethnic meta-analysis (Supplementary Fig. 3).

Replication

Due to the lack of sufficiently large studies on severe Covid-19 disease, reproducibility was sought through a meta-analysis of data from the Covid-19 Host Genetics Initiative (HGI, mixed ancestry) involving 2415 hospitalized Covid-19 cases and 477,741 controls. This included cases reporting being on a ventilator, receiving oxygen, or having pneumonia compared to controls not reporting a positive test. In addition to the already reported locus on chromosome 3 (rs73064425, OR=2.14, discovery p=4.77×10-30), robust replication was found for new associations at four loci identified by GenOMICC: on chromosome 12 within the OAS gene cluster (rs74956615, OR=1.59, discovery p=1.65×10-8), near TYK2 on chromosome 19 (rs74956615, OR=1.59, discovery p=1.65×10-8), within DPP9 on chromosome 19 (rs2109069, OR=1.36, discovery p=3.98×10-12), and on chromosome 21 including the IFNAR2 gene (rs2236757, OR=1.28, discovery p=4.99×10-8) (Fig. 1, Extended Data Table 2).

To enhance the power of exploratory analyses, inverse-variance meta-analysis was conducted between GenOMICC severe EUR (ncases = 1676, ncontrols = 8380), UGI hospitalized Covid-19 vs. population without UK Biobank (B2, version 2) (ncases = 2415, ncontrols = 477741), and 23andMe broad respiratory phenotype (ncases = 1128, ncontrols = 679531). This revealed one additional genome-wide significant (but unreplicated) locus at CCHCR1 (considering no opportunity for replication in the meta-analysis, a stricter threshold of p<10-8 was used) (Table 2).

Mendelian Randomization

Mendelian randomization provides evidence for a causal relationship between an exposure variable and an outcome.18 We used two-sample summary data Mendelian randomization to evaluate evidence supporting the causal effects of RNA expression of various genes (GTEx v7, whole blood) on the odds of severe Covid-19. We identified a priori list of target genes related to the mechanisms of action of many host-targeted drugs proposed for treating Covid-19 (Supplementary Table 3). Among these targets, seven had suitable local expression quantitative trait loci (eQTL) in GTEx (v7). Of these, IFNAR2 remained significant after correcting for multiple testing of the seven tests by Bonferroni correction (β = -1.49, standard error = 0.52, p = 0.0043; Supplementary Table 4). There was uncertain evidence of heterogeneity (HEIDII19 p = 0.015), suggesting that this variant's effect on severe Covid-19 disease may be mediated through a different mechanism, leading to a potential over- or under-estimation of the effect of IFNAR2 expression on the risk of severe disease.

Next, we performed transcriptome-wide Mendelian randomization to quantify the support for non-selected genes as potential therapeutic targets. Instruments were available for 4,614 unique Ensembl gene IDs. After adjusting for multiple comparisons in this analysis, no gene was statistically significant (4,614 tests). After conservatively filtering for heterogeneity (HEIDI p > 0.05), the minimal Mendelian randomization p-value for the variant at chr19:10466123 influencing TYK2 expression was p = 0.00049. Nine other genes with nominally significant Mendelian randomization p-values (p < 0.0051) were advanced for further analysis (Supplementary Table 5).

To replicate these findings, we tested for external evidence using separate eQTL datasets (eQTLgen)20 and GWAS (HGI B2 excluding UK Biobank). Mendelian randomization signals with tentative directional effects were significant for IFNAR2 (p = 7.5×10-4) and TYK2 (p = 5.5×10-5; Supplementary Table 6).

Transcriptome-Wide Association Study

By inferring gene expression from known genetic variants associated with transcript levels (eQTLs), we performed a transcriptome-wide association study (TWAS)21,22 to link GWAS results with tissue-specific gene expression data. This analysis utilized GTEx v8 data from two pre-selected disease-relevant tissues (whole blood and lung) (Figure 2). We selected genes with p < 0.05 in these tissues and incorporated eQTL data from other tissues in GTEx into a composite meta-TWAS analysis23 to optimize the power to detect differences in predicted expression in lung or blood. We identified five genes with genome-wide significant differences in predicted expression (Supplementary Table 7). Among these were four genes with differences in predicted expression in lung tissue (three genes on chr3). We then compared these results with existing biological knowledge about host-virus interactions in Covid-19 using information-based meta-analysis (MAIC)24. The GenOMICC TWAS results overlapped more with transcriptome, proteome, and CRISPR studies of host genes involved in Covid-19 than any other data source (Extended Data Figure 2).

Genetic Correlation

Using the high-definition likelihood (HDL) method25, we initially estimated the SNP-based heritability (the proportion of phenotypic variance captured by additive effects at common SNPs) of severe Covid-19 at 0.065 (SE = 0.019). Two additional analyses did not detect significant signals. The first analysis used controls from the 100,000 Genomes Project, where matching with GenOMICC cases was less close, potentially limiting heritability estimates. The second analysis involved a smaller GWAS comparing some GenOMICC cases to controls from the UK Biobank, matched as closely as possible for BMI and age. This second analysis was less powerful due to the limited number of tightly matched cases (ncases = 1260; ncontrols = 6300; Supplementary Figure 14). Future analyses incorporating a larger number of cases and rare variants should provide more comprehensive heritability estimates. We also examined genetic correlations with other traits, i.e., the extent to which underlying genetic components are shared with severe Covid-19. Using the HDL method, we identified significant negative genetic correlations with educational attainment and intelligence. Additionally, significant positive genetic correlations were detected with several adiposity phenotypes, such as body mass index and fat mass in the legs (Supplementary Figure 19). Furthermore, as seen in GWAS results for other infectious and inflammatory diseases, variants strongly associated with promoters and enhancers were significantly enriched (Supplementary Figure 18).

Discussion

We discovered and replicated significant genetic associations with life-threatening Covid-19 (Figure 1). By focusing on severe cases, some of these associations likely relate to late-stage immune-mediated diseases, such as respiratory failure requiring invasive mechanical ventilation2. Crucially, the genome-wide unbiased nature of GWAS allows for the discovery of entirely novel pathophysiological mechanisms. Genetic variation can be used to infer causality, providing genetic evidence supporting therapeutic targets, thereby substantially increasing the likelihood of successful drug development. Specifically, Mendelian randomization occupies a unique position in the hierarchy of clinical evidence.

Patients admitted to UK intensive care units during the first wave of Covid-19 were, on average, younger and had fewer comorbidities. The cohort studied here is defined by a tendency towards severe respiratory failure caused by Covid-19. In GenOMICC, we recruited from 208 intensive care units (covering 95% of UK ICU capacity) to ensure broad genetic ancestry coverage of UK patients (Extended Data Figure 3).

For external replication, the closest comparisons are the analyses of hospitalized patients and population controls from the Covid-19 Host Genetics Initiative and the broad respiratory phenotype from 23andMe, both generously shared with the international community. Likewise, the complete summary statistics from GenOMICC are immediately available at genomicc.org/data.

Despite differences in case definitions, novel associations identified in studies of severe cases were robustly replicated in combined data from hospitalization studies (Extended Data Table 2). Moreover, Mendelian randomization results suggesting causality for IFNAR2 and TYK2 were statistically significant in confirmatory analyses. Our findings reveal that severe Covid-19 is associated with at least two biological mechanisms: innate antiviral defenses (IFNAR2 and OAS genes) known to be crucial early in disease and host-driven inflammatory lung injury (DPP9, TYK2, and CCR2) central to life-threatening late Covid-19.

Interferons are host antiviral signaling mediators that stimulate the release of many essential components of the early host response to viral infection30. Consistent with the beneficial role of type I interferons, increased expression of the interferon receptor subunit IFNAR2 reduced the odds of severe Covid-19 (Mendelian randomization discovery p = 0.0043 [7 tests]; replication p = 7.5×10-4 [1 test]). Within the assumptions of Mendelian randomization, this represents evidence of a protective role for IFNAR2 in Covid-19. Rare loss-of-function variants in IFNAR2 are associated with severe Covid-1912 and many other viral diseases31,32. This suggests that interferon administration may reduce the likelihood of severe Covid-19, though our evidence cannot distinguish the disease phase where such therapy would be effective. It implies that the genetic effect may be mediated during the early stages of the disease when viral load is high33.

The variant rs10735079 (chr12, p = 1.65 × 10-8) is located in the cluster of interferon-induced oligoadenylate synthetase (OAS) genes (OAS1, OAS2, OAS3; Figure 1). Our TWAS detected a significant association with predicted expression of OAS3 (Figure 2). OAS1 variants have been implicated in SARS-CoV susceptibility in candidate gene association studies conducted in Vietnam34 and China35. These genes encode enzymes that produce the mediator (2',5'-oligoadenylate 2-5A) activating the effector enzyme RNAse L, which degrades double-stranded RNA, a replication intermediate of coronaviruses36. Betacoronaviruses OC43 and MHV produce phosphodiesterases that cleave the host antiviral mediator 2-5A38, but SARS-CoV-2 is not known to possess this capability. OAS genes are potential therapeutic targets since endogenous phosphodiesterase 12 (PDE-12) activity degrades the host antiviral mediator 2-5A39. PDE-12 inhibitors that enhance antiviral activity mediated through OAS are available.

The association at 19p13.3 (rs2109069, p = 3.98 × 10-12) is an intronic variant in the gene encoding dipeptidyl peptidase 9 (DPP9). Variants in this locus are associated with idiopathic pulmonary fibrosis40. DPP9 encodes a serine protease with diverse intracellular functions, including the cleavage of the antiviral signaling molecule CXCL1041, antigen presentation, and activation of inflammatory cells42. Identifying genes that cause inflammatory organ damage is crucial. TYK2 is one of the four genetic targets of JAK inhibitors like baricitinib44, one of the candidate drugs used in our a priori target list (Supplementary Table 3). The association between TYK2 expression and disease severity is confirmed in external datasets.

We reproduce the findings of Ellinghaus et al. at 3p21.31.8. The very small p-values at this locus (p=4.77×10-30) may reflect the larger scale of our study and the focus on extreme severity. Many genes at this locus could potentially explain the association. Systematic review and meta-analysis of experimental data on betacoronavirus infection provided biological support for FYCO145. Our TWAS results indicate that variants in this region significantly affect predicted expression of CXCR6, CCR2, and CCR3 (Figure 2a). One or more of these genes likely mediates the critical pathophysiological mechanism in severe disease.

The association between predicted expression of CCR2 (CC-chemokine receptor 2) and severe disease is particularly strong in lung tissue (Figure 2b). CCR2 promotes monocyte/macrophage chemotaxis to inflammation sites, and its major ligand (monocyte chemoattractant protein/MCP-1) is upregulated in bronchoalveolar lavage fluid from mechanically ventilated Covid-19 patients46. Circulating MCP-1 levels are associated with more severe disease. Anti-CCR2 monoclonal antibody therapy is safe in rheumatoid arthritis47. While the ABO locus has been previously associated with Covid-198, it was not genome-wide significant in our GenOMICC severe cohort48. Interestingly, the combined meta-analysis showed a near genome-wide significant signal at this locus, suggesting that this variant might influence susceptibility to Covid-19 rather than severity (Extended Data Figure 4).

Analysis of shared heritability revealed positive correlations with adiposity traits. This does not suggest causality due to potential biases but likely reflects a combination of two effects. First, increased BMI and lower socioeconomic status are strong risk factors for severe Covid-1914, and second, UK Biobank participants are disproportionately drawn from societal groups underrepresented in obesity49.

Completing and reporting this study urgently necessitated using controls genotyped using different techniques than the cases, drawn from population genetic studies with systematic differences in population structure, demographics, and comorbidities. Residual confounding is reflected in the lambda (λ0.5) values of 1.099 in our primary analysis (Extended Data Figure 1). We mitigated the risk of false-positive associations due to genotyping errors by genotyping the majority of subjects using two different methods (microarray and whole-genome sequencing) and validating significant associations with two additional control groups (100,000 Genomes and Generation Scotland). The success of these mitigations is demonstrated by the robust replication of our sentinel SNPs in external studies. Our meta-analysis combining GenOMICC and multiple additional sources of genome-wide association yielded an encouraging λ0.5 = 1.017 (Extended Data Figure 1).

Further studies to deepen these findings are imperative. Our MAIC results indicate that genes ranked highly in GenOMICC are likely involved in Covid-19 in other studies (Extended Data Figure 2). We continue recruiting into the GenOMICC study, expecting additional associations to be present and detectable with larger case numbers. Future studies using whole-genome sequencing will explore the rarer end of the allele frequency spectrum for variants that increase susceptibility. Given that the GenOMICC cohort is strongly enriched for immediately life-threatening disease, defined by patients receiving invasive mechanical ventilation or judged by the treating clinician as being at high risk of requiring mechanical support, effect sizes are likely to be larger.

We discovered novel genetic associations with severe Covid-19. Some of these associations directly lead to potential therapeutic approaches, such as augmenting interferon signaling, antagonizing monocyte activation and infiltration into the lung, or specifically targeting detrimental inflammatory pathways. This significantly contributes to the biological rationale supporting specific treatments, but each must be tested in large clinical trials before incorporation into clinical practice.

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Methods, Additional References, Nature Research Reporting Summary, Source Data, Extended Data, Supplementary Information, Acknowledgements, Peer Review Information, Author Contributions and Competing Interests, Data and Code Availability statements are available at https://doi.org/10.1038/s41586-020-03065-y.

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© The Author(s), published under an exclusive license to Springer Nature Limited 2020.

¹Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, EH25 9RG, UK. ²MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. ³Genomics England, London, UK. ⁴Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK. ⁵Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. ⁶Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, EH4 2XU, UK. ⁷Intensive Care National Audit & Research Centre, London, UK. ⁸Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. ⁹Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. ¹⁰The Crick Institute, London, UK. ¹¹Intensive Care Unit, Royal Infirmary of Edinburgh, 54 Little France Drive, Edinburgh, EH16 5SA, UK. ¹²School of Life Sciences, Westlake University, Hangzhou, Zhejiang, 310024, China. ¹³Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, 310024, China. ¹⁴Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. ¹⁵Department of Medicine, University of Cambridge, Cambridge, UK. ¹⁶Department of Intensive Care Medicine, Guy’s and St. Thomas NHS Foundation Trust, London, UK. ¹⁷School of Immunology and Microbial Sciences, King’s College London, London, UK. ¹⁸NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of Liverpool, Liverpool, L69 7BE, UK. ¹⁹MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. ²⁰William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. ²¹Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7FZ, UK. ²²Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, Ireland. ²³Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia. ²⁴Intensive Care Unit, Alfred Hospital, Melbourne, Victoria, Australia. ²⁵Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, Kingston, Ontario, Canada. ²⁶Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. ²⁷Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK. ²⁸Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, UK. ²⁹UCL Centre for Human Health and Performance, London, W1T 7HA, UK. ³⁰Faculty of Medicine, University of São Paulo, São Paulo, Brazil. ³¹Medical Genetics, University of Siena, Siena, Italy. ³²Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy. ³³Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Teviot Place, Edinburgh, EH8 9AG, UK. ³⁴Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. ³⁵Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. ³⁶National Heart and Lung Institute, Imperial College London, London, UK. ³⁷Imperial College Healthcare NHS Trust London, London, UK. ³⁸Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK. ³²⁵These authors contributed equally. Additionally, such studies invite the collaboration of researchers. *A list of authors and affiliations is available in the online version of the paper. ✉e-mail: j.k.baillie@ed.ac.uk

図1 ディスカバリーGWASとメタ解析の結果 — **Figure 1** Discovery GWAS and meta-analysis results. The Miami plot shows the p-values from the GenOMICC GWAS in EUR (after validation, top panel) and the meta-analysis including patients from the Covid-19 Host Genetics Initiative and 23andMe (bottom panel). Unadjusted p-values from the GWAS analysis are shown. In the top panel (GenOMICC), the red horizontal line indicates genome-wide significance for common variants at -log10(5×10^-8), and in the bottom panel (meta-analysis), the red horizontal line indicates a more stringent genome-wide significance threshold for meta-analysis variants at -log10(10^-8). Quantile-quantile (QQ) plots, shown in the insets, display observed versus expected p-values to indicate the genomic inflation factor (λ) for each analysis. For GenOMICC EUR, λ = 1.099; for the GenOMICC-HGI-23m meta-analysis, λ = 1.017. Complete QQ plots are available in Extended Data Figure 1.

図2 TWAS結果の概要 — **Figure 2** Overview of TWAS results.
a. Gene-level Manhattan plot showing the raw p-value results from a cross-tissue meta-TWAS analysis (see Methods). The z-scores indicate the direction of effect of genotype-imputed expression of protein-coding gene transcripts in lung tissue (GTEX v8). The red highlights indicate genome-wide significance at p < 5 × 10^-6.

Table 1 Lead Variants from Independent Genome-Wide Significant Regions

SNP	chr:pos(b37)	Risk	Alt	RAFgcc	RAFukb	OR	CI	Pgcc.ukb	Pgcc.gs	Pgcc.100k	Locus
rs73064425	3:45901089	T	C	0.15	0.07	2.1	1.88-2.45	4.8x10^-30	2.9x10^-27	3.6x10^-32	LZTFL1
rs9380142	6:29798794	A	G	0.74	0.69	1.3	1.18-1.43	3.2x10^-8	0.00091	1.8x10^-8	HLA-G
rs143334143	6:31121426	A	G	0.12	0.07	1.9	1.61-2.13	8.8x10^-18	2.6x10^-24	5.8x10^-18	CCHCR1
rs3131294	6:32180146	G	A	0.9	0.86	1.5	1.28-1.66	2.8x10^-8	1.3x10^-10	2.3x10^-8	NOTCH4
rs10735079	12:113380008	A	G	0.68	0.63	1.3	1.18-1.42	1.6x10^-8	2.8x10^-9	4.7x10^-6	OAS1/3
rs2109069	19:4719443	A	G	0.38	0.32	1.4	1.25-1.48	4x10^-12	4.5x10^-7	2.4x10^-8	DPP9
rs74956615	19:10427721	A	T	0.079	0.05	1.6	1.35-1.87	2.3x10^-8	2.2x10^-13	3.9x10^-6	TYK2
rs2236757	21:34624917	A	G	0.34	0.28	1.3	1.17-1.41	5x10^-8	8.9x10^-5	8.3x10^-7	IFNAR2

chr:pos - Chromosome and position of the top SNP (build 37); Risk - Risk allele; Alt - Alternative allele; RAF - Risk allele frequency; OR - Effect size (odds ratio) of the risk allele in the GenOMICC EUR analysis; CI - 95% confidence interval of the odds ratio in the GenOMICC EUR cohort; P - p-value; Locus - Gene nearest to the top SNP. Subscript identifiers indicate the cohorts used for the cases: gcc - GenOMICC EUR; and the controls: ukb - UK Biobank; gs - Generation Scotland; 100k - 100,000 Genomes.

Table 2 Meta-analysis of overlapping SNPs between GenOMICC (EUR) and HGI (hospitalized Covid-19 vs. population) and 23andMe studies

SNP	chr:pos(b37)	Risk	Alt	ORgcc	CIgcc	Pgcc	ORmeta	CImeta	Pmeta	Locus
rs71325088	3:45862952	C	T	2.1	1.87-2.43	9.3x10^-30	1.9	1.73-2	2.5x10^-54	LZTFL1
rs143334143	6:31121426	A	G	1.8	1.61-2.13	8.8x10^-18	1.3	1.27-1.48	1.5x10^-10	CCHCR1
rs6489867	12:113363550	T	C	1.3	1.15-1.37	6.9x10^-7	1.2	1.14-1.25	9.7x10^-10	OAS1
rs2109069	19:4719443	A	G	1.4	1.25-1.48	4x10^-12	1.2	1.19-1.31	7x10^-13	DPP9
rs11085727	19:10466123	T	C	1.3	1.17-1.4	1.3x10^-7	1.2	1.18-1.31	1.2x10^-13	TYK2
rs13050728	21:34615210	T	C	1.3	1.15-1.38	3x10^-7	1.2	1.16-1.28	5.1x10^-12	IFNAR2

This is a meta-analysis of all available data; therefore, SNPs are included in this table if they meet a more stringent p-value threshold of p<10^-8, as an attempt at external replication cannot be made. SNP - the strongest SNP within the locus; Risk - risk allele; Alt - alternative allele; OR - odds ratio of the risk allele; CI - 95% confidence interval of the odds ratio; Locus - gene closest to the top SNP. Subscript identifiers denote gcc - GenOMICC study, European ancestry, comparison with UK Biobank, meta-analysis of European ancestry cases across all three studies (GenOMICC, HGI, 23andMe).

GenOMICC Consortium

GenOMICC Collaborators

Sara Clohisey¹, Peter Horby²¹, Johnny Millar¹, Julian Knight¹⁴, Hugh Montgomery²⁹, David Maslove²⁵, Lowell Ling²⁶, Alistair Nichol²², Charlotte Summers¹⁵, Tim Walsh¹¹, Charles Hinds²⁰, Malcolm G. Semple^18,38, Peter J.M. Openshaw^36,37, Manu Shankar-Hari¹⁶, Antonia Ho¹⁹, Danny McAuley^27,28, Chris Ponting², Kathy Rowan⁷ & J. Kenneth Baillie^1,2,11

Central management and laboratory team

Fiona Griffiths¹, Wilna Oosthuyzen¹, Jen Meikle¹, Paul Finernan¹, James Furniss¹, Ellie Mcmaster¹, Andy Law¹, Sara Clohisey¹, J. Kenneth Baillie^1,11, Trevor Paterson¹, Tony Wackett¹, Ruth Armstrong¹, Lee Murphy⁶, Angie Fawkes⁶, Richard Clark⁶, Audrey Coutts⁶, Lorna Donnelly⁶, Tammy Gilchrist⁶, Katarzyna Hafezi⁶, Louise Macgillivray⁶, Alan Maclean⁶, Sarah McCafferty⁶, Kirstie Morrice⁶, Jane Weaver¹, Ceilia Boz¹, Ailsa Golightly¹, Mari Ward¹, Hanning Mal¹, Helen Szoor-McElhinney¹, Adam Brown¹, Ross Hendry¹, Andrew Stenhouse¹, Louise Cullum¹, Dawn Law¹, Sarah Law¹, Rachel Law¹, Max Head Fourman¹, Maaike Swets¹, Nicky Day¹, Filip Taneski¹, Esther Duncan¹, Marie Zechner¹ & Nicholas Parkinson¹

Data analysis team

Erola Pairo-Castineira^1,2, Sara Clohisey¹, Lucija Klaric², Andrew D. Bretherick², Konrad Rawlik¹, Dorota Pasko³, Susan Walker³, Nick Parkinson¹, Max Head Fourman¹, Clark D Russell^1,4, James Furniss¹, Anne Richmond², Elvina Gountouna⁵, David Harrison⁷, Bo Wang¹, Yang Wu⁸, Alison Meynert², Athanasios Kousathanas³, Loukas Moutsianas³, Zhijian Yang⁹, Ranran Zhai⁹, Chenqing Zheng⁹, Graeme Grimes², Jonathan Millar¹, Barbara Shih¹, Marie Zechner¹, Jian Yang^12,13, Xia Shen^9,33,34, Chris P. Ponting², Albert Tenesa^1,2,33, Kathy Rowan⁷, Andrew Law¹, Veronique Vitart², James F. Wilson^2,33, J. Kenneth Baillie^1,2,11

Barts Health NHS Trust, London, UK

D. Collier³⁹, S. Wood³⁹, A. Zak³⁹, C. Borra³⁹, M. Matharu³⁹, P. May³⁹, Z. Alldis³⁹, O. Mitchelmore³⁹, R. Bowles³⁹, A. Easthorpe³⁹, F. Bibi³⁹, I. Lancoma-Malcolm³⁹, J. Gurasashvili³⁹, J. Pheby³⁹, J. Shiel³⁹, M. Bolton³⁹, M. Patel³⁹, M. Taylor³⁹, O. Zongo³⁹, P. Ebano³⁹, P. Harding³⁹, R. Astin-Chamberlain³⁹, Y. Choudhury³⁹, A. Cox³⁹, D. Kallon³⁹, M. Burton³⁹, R. Hall³⁹, S. Blowes³⁹, Z. Prime³⁹, J. Biddle³⁹, O. Prysyazhna³⁹, T. Newman³⁹, C. Tierney³⁹ & J. Kassam³⁹

Guys and St Thomas’ Hospital, London, UK

M. Shankar-Hari⁴⁰, M. Ostermann⁴⁰, S. Campos⁴⁰, A. Bociek⁴⁰, R. Lim⁴⁰, N. Grau⁴⁰, T. O. Jones⁴⁰, C. Whitton⁴⁰, M. Marotti⁴⁰ & G. Arbane⁴⁰

James Cook University Hospital, Middlesburgh, UK

S. Bonner⁴¹, K. Hugill⁴¹ & J. Reid⁴¹

The Royal Liverpool University Hospital, Liverpool, UK

I. Welters⁴², V. Waugh⁴², K. Williams⁴², D. Shaw⁴², J. Fernandez Roman⁴², M. Lopez Martinez⁴², E. Johnson⁴², A. Waite⁴², B. Johnson⁴², O. Hamilton⁴² & S. Mulla⁴²

King’s College Hospital, London, UK

M. McPhail⁴³ & J. Smith⁴³

Royal Infirmary of Edinburgh, Edinburgh, UK

J. K. Baillie^1,2,11, L. Barclay⁴⁴, D. Hope⁴⁴, C. McCulloch⁴⁴, L. McQuillan⁴⁴, S. Clark⁴⁴, J. Singleton⁴⁴, K. Priestley⁴⁴, N. Rea⁴⁴, M. Callaghan⁴⁴, R. Campbell⁴⁴, G. Andrew⁴⁴ & L. Marshall⁴⁴

John Radcliffe Hospital, Oxford, UK

S. McKechnie⁴⁵, P. Hutton⁴⁵, A. Bashyal⁴⁵ & N. Davidson⁴⁵

Addenbrooke’s Hospital, Cambridge, UK

C. Summers⁴⁶, P. Polgarova⁴⁶, K. Stroud⁴⁶, N. Pathan⁴⁶, K. Elston⁴⁶ & S. Agrawal⁴⁶

Morriston Hospital, Swansea, UK

C. Battle⁴⁷, L. Newey⁴⁷, T. Rees⁴⁷, R. Harford⁴⁷, E. Brinkworth⁴⁷, M. Williams⁴⁷ & C. Murphy⁴⁷

Ashford and St Peter’s Hospital, Surrey, UK

I. White⁴⁸ & M. Croft⁴⁸

Royal Stoke University Hospital, Staffordshire, UK

N. Bandla⁴⁹, M. Gellamucho⁴⁹, J. Tomlinson⁴⁹, H. Turner⁴⁹, M. Davies⁴⁹, A. Quinn⁴⁹, I. Hussain⁴⁹, C. Thompson⁴⁹, H. Parker⁴⁹, R. Bradley⁴⁹ & R. Griffiths⁴⁹

Queen Elizabeth Hospital, Birmingham, UK

J. Scriven⁵⁰ & J. Gill⁵⁰

Glasgow Royal Infirmary, Glasgow, UK

A. Puxty⁵¹, S. Cathcart⁵¹, D. Salutous⁵¹, L. Turner⁵¹, K. Duffy⁵¹ & K. Puxty⁵¹

Kingston Hospital, Surrey, UK

A. Joseph⁵², R. Herdman-Grant⁵², R. Simms⁵², A. Swain⁵², A. Naranjo⁵², R. Crowe⁵²,K. Sollesta⁵², A. Loveridge⁵², D. Baptista⁵² & E. Morino⁵²

The Tunbridge Wells Hospital and Maidstone Hospital, Kent, UK

M. Davey⁵³, D. Golden⁵³ & J. Jones⁵³

North Middlesex University Hospital NHS Trust, London, UK

J. Moreno Cuesta⁵⁴, A. Haldeos⁵⁴, D. Bakthavatsalam⁵⁴, R. Vincent⁵⁴, M. Elhassan⁵⁴,K. Xavier⁵⁴, A. Ganesan⁵⁴ & D. Purohit M. Abdelrazik⁵⁴

Bradford Royal Infirmary, Bradford, UK

J. Morgan⁵⁵, L. Akeroyd⁵⁵, S. Bano⁵⁵, D. Warren⁵⁵, M. Bromley⁵⁵, K. Sellick⁵⁵, L. Gurr⁵⁵,B. Wilkinson⁵⁵, V. Nagarajan⁵⁵ & P. Szedlak⁵⁵

Blackpool Victoria Hospital, Blackpool, UK

J. Cupitt⁵⁶, E. Stoddard⁵⁶, L. Benham⁵⁶, S. Preston⁵⁶, N. Slawson⁵⁶, Z. Bradshaw⁵⁶, J. brown⁵⁶,M. Caswell⁵⁶ & S. Melling⁵⁶

Countess of Chester Hospital, Chester, UK

P. Bamford⁵⁷, M. Faulkner⁵⁷, K. Cawley⁵⁷, H. Jeffrey⁵⁷, E. London⁵⁷, H. Sainsbury⁵⁷, I. Nagra⁵⁷,F. Nasir⁵⁷, Ce Dunmore⁵⁷, R. Jones⁵⁷, A. Abraheem⁵⁷, M. Al-Moasseb⁵⁷ & R. Girach⁵⁷

Wythenshawe Hospital, Manchester, UK

C. Brantwood⁵⁸, P. Alexander⁵⁸, J. Bradley-Potts⁵⁸, S. Allen⁵⁸ & T. Felton⁵⁸

St George’s Hospital, London, UK

S. Manna⁵⁹, S. Farnell-Ward⁵⁹, S. Leaver⁵⁹, J. Queiroz⁵⁹, E. Maccacari⁵⁹, D. Dawson⁵⁹, C. Castro Delgado⁵⁹, R. Pepermans Saluzzio⁵⁹, O. Ezeobu⁵⁹, L. Ding⁵⁹, C. Sicat⁵⁹, R. Kanu⁵⁹, G. Durrant⁵⁹, J. Texeira⁵⁹, A. Harrison⁵⁹ & T. Samakomva⁵⁹

Good Hope Hospital, Birmingham, UK

J. Scriven⁶⁰, H. Willis⁶⁰, B. Hopkins⁶⁰ & L. Thrasyvoulou⁶⁰

Stepping Hill Hospital, Stockport, UK

M. Jackson⁶¹, A. Zaki⁶¹, C. Tibke⁶¹, S. Bennett⁶¹, W. Woodyatt⁶¹, A. Kent⁶¹ & E. Goodwin⁶¹

Manchester Royal Infirmary, Manchester, UK

C. Brandwood⁶², R. Clark⁶² & L. Smith⁶²

Royal Alexandra Hospital, Paisley, UK

K. Rooney⁶³, N. Thomson⁶³, N. Rodden⁶³, E. Hughes⁶³, D. McGlynn⁶³, C. Clark⁶³, P. Clark⁶³, L. Abel⁶³, R. Sundaram⁶³, L. Gemmell⁶³, M. Brett⁶³, J. Hornsby⁶³, P. MacGoey⁶³, R. Price⁶³, B. Digby⁶³, P. O’Neil⁶³, P. McConnell⁶³ & P. Henderson⁶³

Queen Elizabeth University Hospital, Glasgow, UK

S. Henderson⁶⁴, M. Sim⁶⁴, S. Kennedy-Hay⁶⁴, C. McParland⁶⁴, L. Rooney⁶⁴ & N. Baxter⁶⁴

Queen Alexandra Hospital, Portsmouth, UK

D. Pogson⁶⁵, S. Rose⁶⁵, Z. Daly⁶⁵ & L. Brimfield⁶⁵

BHRUT (Barking Havering) - Queens Hospital and King George Hospital, Essex, UK

M. K. Phull⁶⁶, M. Hussain⁶⁶, T. Pogreban⁶⁶, L. Rosaroso⁶⁶ & E. Salciute L. Grauslyte⁶⁶

University College Hospital, London, UK

D. Brealey⁶⁷, E. Wraith⁶⁷, N. MacCallum⁶⁷, G. Bercades⁶⁷, I. Hass⁶⁷, D. Smyth⁶⁷, A. Reyes⁶⁷ & G. Martir⁶⁷

Royal Victoria Infirmary, Newcastle Upon Tyne, UK

I. D. Clement⁶⁸, K. Webster⁶⁸, C. Hays⁶⁸ & A. Gulati⁶⁸

Western Sussex Hospitals, West Sussex, UK

L. Hodgson⁶⁹, M. Margarson⁶⁹, R. Gomez⁶⁹, Y. Baird⁶⁹, Y. Thirlwall⁶⁹, L. Folkes⁶⁹, A. Butler⁶⁹, E. Meadows⁶⁹, S. Moore⁶⁹, D. Raynard⁶⁹, H. Fox⁶⁹, L. Riddles⁶⁹, K. King⁶⁹, S. Kimber⁶⁹, G. Hobden⁶⁹, A. McCarthy⁶⁹, V. Cannons⁶⁹, I. Balagosa⁶⁹, I. Chadbourn⁶⁹ & A. Gardner⁶⁹

Salford Royal Hospital, Manchester, UK

D. Horner⁷⁰, D. McLaughlanv⁷⁰, B. Charles⁷⁰, N. Proudfoot⁷⁰, T. Marsden⁷⁰, L. Mc Morrow⁷⁰, B. Blackledge⁷⁰, J. Pendlebury⁷⁰, A. Harvey⁷⁰, E. Apetri⁷⁰, C. Basikolo⁷⁰, L. Catlow⁷⁰, R. Doonan⁷⁰, K. Knowles⁷⁰, S. Lee⁷⁰, D. Lomas⁷⁰, C. Lyons⁷⁰, J. Perez⁷⁰, M. Poulaka⁷⁰, M. Slaughter⁷⁰, K. Slevin⁷⁰, M. Taylor⁷⁰, V. Thomas⁷⁰, D. Walker⁷⁰ & J. Harris⁷⁰

The Royal Oldham Hospital, Manchester, UK

A. Drummond⁷¹, R. Tully⁷¹, J. Dearden⁷¹, J. Philbin⁷¹, S. Munt⁷¹, C. Rishton⁷¹, G. O’Connor⁷¹, M. Mulcahy⁷¹, E. Dobson⁷¹, J. Cuttler⁷¹ & M. Edward⁷¹

Pinderfields General Hospital, Wakefield, UK

A. Rose⁷², B. Sloan⁷², S. Buckley⁷², H. Brooke⁷², E. Smithson⁷², R. Charlesworth⁷², R. Sandu⁷², M. Thirumaran⁷², V. Wagstaff⁷² & J. Cebrian Suarez⁷²

Basildon Hospital, Basildon, UK

A. Kaliappan⁷³, M. Vertue⁷³, A. Nicholson⁷³, J. Riches⁷³, A. Solesbury⁷³, L. Kittridge⁷³, M. Forsey⁷³ & G. Maloney⁷³

University Hospital of Wales, Cardiff, UK

J. Cole⁷⁴, M. Davies⁷⁴, R. Davies⁷⁴, H. Hill⁷⁴, E. Thomas⁷⁴, A. Williams⁷⁴, D. Duffin⁷⁴ & B. Player⁷⁴

Broomfield Hospital, Chelmsford, UK

J. Radhakrishnan⁷⁵, S. Gibson⁷⁵, A. Lyle⁷⁵ & F. McNeela⁷⁵

Royal Brompton Hospital, London, UK

B. Patel⁷⁶, M. Gummadi⁷⁶, G. Sloane⁷⁶, N. Dormand⁷⁶, S. Salmi⁷⁶, Z. Farzad⁷⁶, D. Cristiano⁷⁶, K. Liyanage⁷⁶, V. Thwaites⁷⁶ & M. Varghese⁷⁶

Nottingham University Hospital, Nottingham, UK

M. Meredith⁷

Royal Hallamshire Hospital and Northern General Hospital, Sheffield, UK

G. Mills⁷⁸, J. Willson⁷⁸, K. Harrington⁷⁸, B. Lenagh⁷⁸, K. Cawthron⁷⁸, S. Masuko⁷⁸, A. Raithatha⁷⁸, K. Bauchmuller⁷⁸, N. Ahmad⁷⁸, J. Barker⁷⁸, Y. Jackson⁷⁸, F. Kibutu⁷⁸ & S. Bird⁷⁸

Royal Hampshire County Hospital, Hampshire, UK

G. Watson⁷⁹, J. Martin⁷⁹, E. Bevan⁷⁹, C. Wrey Brown⁷⁹ & D. Trodd⁷⁹

Queens Hospital Burton, Burton-On-Trent, UK

K. English⁸⁰, G. Bell⁸⁰, L. Wilcox⁸⁰ & A. Katary⁸⁰

New Cross Hospital, Wolverhampton, UK

S. Gopal⁸¹, V. Lake⁸¹, N. Harris⁸¹, S. Metherell⁸¹ & E. Radford⁸¹

Heartlands Hospital, Birmingham, UK

J. Scriven⁸², F. Moore⁸², H. Bancroft⁸², J. Daglish⁸², M. Sangombe⁸², M. Carmody⁸², J. Rhodes⁸² & M. Bellamy⁸²

Walsall Manor Hospital, Walsall, UK

A. Garg⁸³, A. Kuravi⁸³, E. Virgilio⁸³, P. Ranga⁸³, J. Butler⁸³, L. Botfield⁸³, C. Dexter⁸³ & J. Fletcher⁸³

Stoke Mandeville Hospital, Buckinghamshire, UK

P. Shanmugasundaram⁸⁴, G. Hambrook⁸⁴, I. Burn⁸⁴, K. Manso⁸⁴, D. Thornton⁸⁴, J. Tebbutt⁸⁴ & R. Penn⁸⁴

Sandwell General Hospital, Birmingham, UK

J. Hulme⁸⁵, S. Hussain⁸⁵, Z. Maqsood⁸⁵, S. Joseph⁸⁵, J. Colley⁸⁵, A. Hayes⁸⁵, C. Ahmed⁸⁵, R. Haque⁸⁵, S. Clamp⁸⁵, R. Kumar⁸⁵, M. Purewal⁸⁵ & B. Baines⁸⁵

Royal Berkshire NHS Foundation Trust, Berkshire, UK

M. Frise⁸⁶, N. Jacques⁸⁶, H. Coles⁸⁶, J. Caterson⁸⁶, S. Gurung Rai⁸⁶, M. Brunton⁸⁶, E. Tilney⁸⁶, L. Keating⁸⁶ & A. Walden⁸⁶

Charing Cross Hospital, St Mary’s Hospital and Hammersmith Hospital, London, UK

D. Antcliffe⁸⁷, A. Gordon⁸⁷, M. Templeton⁸⁷, R. Rojo⁸⁷, D. Banach⁸⁷, S. Sousa Arias⁸⁷, Z. Fernandez⁸⁷ & P. Coghlan⁸⁷

Dumfries and Galloway Royal Infirmary, Dumfries, UK

D. Williams⁸⁸ & C. Jardine⁸⁸

Bristol Royal Infirmary, Bristol, UK

J. Bewley⁸⁹, K. Sweet⁸⁹, L. Grimmer⁸⁹, R. Johnson⁸⁹, Z. Garland⁸⁹ & B. Gumbrill⁸⁹

Royal Sussex County Hospital, Brighton, UK

C. Phillips⁹⁰, L. Ortiz-Ruiz de Gordoa⁹⁰ & E. Peasgood⁹⁰

Whiston Hospital, Prescot, UK

A. Tridente⁹¹ & K. Shuker S. Greer⁹¹

Royal Glamorgan Hospital, Cardiff, UK

C. Lynch⁹², C. Pothecary⁹², L. Roche⁹², B. Deacon⁹², K. Turner⁹², J. Singh⁹² & G. Sera Howe⁹²

King’s Mill Hospital, Nottingham, UK

P. Paul⁹³, M. Gill⁹³, I. Wynter⁹³, V. Ratnam⁹³ & S. Shelton⁹³

Fairfield General Hospital, Bury, UK

J. Naisbitt⁹⁴ & J. Melville⁹⁴

Western General Hospital, Edinburgh, UK

R. Baruah⁹⁵ & S. Morrison⁹⁵

Northwick Park Hospital, London, UK

A. McGregor⁹⁶, V. Parris⁹⁶, M. Mpelembue⁹⁶, S. Srikaran⁹⁶, C. Dennis⁹⁶ & A. Sukha⁹⁶

Royal Preston Hospital, Preston, UK

A. Williams⁹⁷ & M. Verlande⁹⁷

Royal Derby Hospital, Derby, UK

K. Holding⁹⁸, K. Riches⁹⁸, C. Downes⁹⁸ & C. Swan⁹⁸

Sunderland Royal Hospital, Sunderland, UK

A. Rostron⁹⁹, A. Roy⁹⁹, L. Woods⁹⁹, S. Cornell⁹⁹ & F. Wakinshaw⁹⁹

Royal Surrey County Hospital, Guildford, UK

B. Creagh-Brown¹⁰⁰, H. Blackman¹⁰⁰, A. Salberg¹⁰⁰, E. Smith¹⁰⁰, S. Donlon¹⁰⁰, S. Mtuwa¹⁰⁰,
N. Michalak-Glinska¹⁰⁰, S. Stone¹⁰⁰, C. Beazley¹⁰⁰ & V. Pristopan¹⁰⁰

Derriford Hospital, Plymouth, UK

N. Nikitas¹⁰¹, L. Lankester¹⁰¹ & C. Wells¹⁰¹

Croydon University Hospital, Croydon, UK

A. S. Raj¹⁰², K. Fletcher¹⁰², R. Khade¹⁰² & G. Tsinaslanidis¹⁰²

Victoria Hospital, Kirkcaldy, UK

M. McMahon¹⁰³, S. Fowler¹⁰³, A. McGregor¹⁰³ & T. Coventry¹⁰³

Milton Keynes University Hospital, Milton Keynes, UK

R. Stewart¹⁰⁴, L. Wren¹⁰⁴, E. Mwaura¹⁰⁴, L. Mew¹⁰⁴, A. Rose¹⁰⁴, D. Scaletta¹⁰⁴ & F. Williams¹⁰⁴

Barnsley Hospital, Barnsley, UK

K. Inweregbu¹⁰⁵, A. Nicholson¹⁰⁵, N. Lancaster¹⁰⁵, M. Cunningham¹⁰⁵, A. Daniels¹⁰⁵, L. Harrison¹⁰⁵, S. Hope¹⁰⁵, S. Jones¹⁰⁵, A. Crew¹⁰⁵, G. Wray¹⁰⁵, J. Matthews¹⁰⁵ & R. Crawley¹⁰⁵

York Hospital, York, UK

J. Carter¹⁰⁶, I. Birkinshaw¹⁰⁶, J. Ingham¹⁰⁶, Z. Scott¹⁰⁶, K. Howard¹⁰⁶, R. Joy¹⁰⁶ & S. Roche¹⁰⁶

University Hospital of North Tees, Stockton on Tees, UK

M. Clark¹⁰⁷ & S. Purvis¹⁰⁷

University Hospital Wishaw, Wishaw, UK

A. Morrison¹⁰⁸, D. Strachan¹⁰⁸, M. Taylor¹⁰⁸, S. Clements¹⁰⁸ & K. Black¹⁰⁸

Whittington Hospital, London, UK

C. Parmar¹⁰⁹, A. Altabaibeh¹⁰⁹, K. Simpson¹⁰⁹, L. Mostoles¹⁰⁹, K. Gilbert¹⁰⁹, L. Ma¹⁰⁹ & A. Alvaro¹⁰⁹

Southmead Hospital, Bristol, UK

M. Thomas¹¹⁰, B. Faulkner¹¹⁰, R. Worner¹¹⁰, K. Hayes¹¹⁰, E. Gendall¹¹⁰, H. Blakemore¹¹⁰, B. Borislavova¹¹⁰ & E. Goff¹¹⁰

The Royal Papworth Hospital, Cambridge, UK

A. Vuylsteke¹¹¹, L. Mwaura¹¹¹, J. Zamikula¹¹¹, L. Garner¹¹¹, A. Mitchell¹¹¹, S. Mepham¹¹¹, L. Cagova¹¹¹, A. Fofano¹¹¹, H. Holcombe¹¹¹ & K. Praman¹¹¹

Royal Gwent Hospital, Newport, UK

T. Szakmany¹¹², A. E. Heron¹¹², S. Cherian¹¹², S. Cutler¹¹² & A. Roynon-Reed¹¹²

Norfolk and Norwich University hospital (NNUH), Norwich, UK

G. Randell¹¹³, K. Convery¹¹³, K. Stammers D. Fottrell-Gould¹¹³, L. Hudig¹¹³ & J. Keshet-price¹¹³

Great Ormond St Hospital and UCL Great Ormond St Institute of Child Health NIHR

Biomedical Research Centre, London, UK

M. Peters¹¹⁴, L. O’Neill¹¹⁴, S. Ray¹¹⁴, H. Belfield¹¹⁴, T. McHugh¹¹⁴, G. Jones¹¹⁴, O. Akinkugbe¹¹⁴, A. Tomas¹¹⁴, E. Abaleke¹¹⁴, E. Beech¹¹⁴, H. Meghari¹¹⁴, S. Yussuf¹¹⁴ & A. Bamford¹¹⁴

Airedale General Hospital, Keighley, UK

B. Hairsine¹¹⁵, E. Dooks¹¹⁵, F. Farquhar¹¹⁵, S. Packham¹¹⁵, H. Bates¹¹⁵, C. McParland¹¹⁵ & L. Armstrong¹¹⁵

Aberdeen Royal Infirmary, Aberdeen, UK

C. Kaye¹¹⁶, A. Allan¹¹⁶, J. Medhora¹¹⁶, J. Liew¹¹⁶, A. Botello¹¹⁶ & F. Anderson¹¹⁶

Southampton General Hospital, Southampton, UK

R. Cusack¹¹⁷, H. Golding¹¹⁷, K. Prager¹¹⁷, T. Williams¹¹⁷, S. Leggett¹¹⁷, K. Golder¹¹⁷, M. Male¹¹⁷, O. Jones¹¹⁷, K. Criste¹¹⁷ & M. Marani¹¹⁷

Russell’s Hall Hospital, Dudley, UK

Dr Anumakonda¹¹⁸, V. Amin¹¹⁸, K. Karthik¹¹⁸, R. Kausar¹¹⁸, E. Anastasescu¹¹⁸, K. Reid¹¹⁸ & Ms Jacqui¹¹⁸

Rotherham General Hospital, Rotherham, UK

A. Hormis¹¹⁹, R. Walker¹¹⁹ & D. Collier¹¹⁹

North Manchester General Hospital, Manchester, UK

T. Duncan¹²⁰, A. Uriel¹²⁰, A. Ustianowski¹²⁰, H. T-Michael¹²⁰, M. Bruce¹²⁰, K. Connolly¹²⁰ & K. Smith¹²⁰

Basingstoke and North Hampshire Hospital, Basingstoke, UK

R. Partridge¹²¹, D. Griffin¹²¹, M. McDonald¹²¹ & N. Muchenje¹²¹

Royal Free Hospital, London, UK

D. Martin¹²², H. Filipe¹²², C. Eastgate¹²² & C. Jackson¹²²

Hull Royal Infirmary, Hull, UK

A. Gratrix¹²³, L. Foster¹²³, V. Martinson¹²³, E. Stones¹²³, Caroline Abernathy¹²³ & P. Parkinson¹²³

Harefield Hospital, London, UK

A. Reed¹²⁴, C. Prendergast¹²⁴, P. Rogers¹²⁴, M. Woodruff¹²⁴, R. Shokkar¹²⁴, S. Kaul¹²⁴, A. Barron¹²⁴ & C. Collins¹²⁴

Chesterfield Royal Hospital Foundation Trust, Chesterfield, UK

S. Beavis¹²⁵, A. Whileman¹²⁵, K. Dale¹²⁵, J. Hawes¹²⁵, K. Pritchard¹²⁵, R. Gascoyne¹²⁵ & L. Stevenson¹²⁵

Barnet Hospital, London, UK

R. Jha¹²⁶, L. Lim¹²⁶ & V. Krishnamurthy¹²⁶

Aintree University Hospital, Liverpool, UK

R. Parker¹²⁷, I. Turner-Bone¹²⁷, L. Wilding¹²⁷ & A. Reddy¹²⁷

St James’s University Hospital and Leeds General Infirmary, Leeds, UK

S. Whiteley¹²⁸, E. Wilby¹²⁸, C. Howcroft¹²⁸, A. Aspinwall¹²⁸, S. Charlton¹²⁸ & B. Ogg¹²⁸

Glan Clwyd Hospital, Bodelwyddan, UK

D. Menzies¹²⁹, R. Pugh¹²⁹, E. Allan¹²⁹, R. Lean¹²⁹, F. Davies¹²⁹, J. Easton¹²⁹, X. Qiu¹²⁹, S. Kumar¹²⁹ & K. Darlington129

University Hospital Crosshouse, Kilmarnock, UK

G. Houston¹³⁰, P. O’Brien¹³⁰, T. Geary¹³⁰, J. Allan¹³⁰ & A. Meikle¹³⁰

Royal Bolton Hospital, Bolton, UK

G. Hughes¹³¹, M. Balasubramaniam¹³¹, S. Latham¹³¹, E. McKenna¹³¹ & R. Flanagan¹³¹

Princess of Wales Hospital, Llantrisant, UK

S. Sathe¹³², E. Davies¹³² & L. Roche¹³²

Pilgrim Hospital, Lincoln, UK

M. Chablani¹³³, A. Kirkby¹³³, K. Netherton¹³³ & S. Archer¹³³

Northumbria Healthcare NHS Foundation Trust, North Shields, UK

B. Yates¹³⁴ & C. Ashbrook-Raby¹³⁴

Ninewells Hospital, Dundee, UK

S. Cole¹³⁵, M. Casey¹³⁵, L. Cabrelli¹³⁵, S. Chapman¹³⁵, M. Casey¹³⁵, A. Hutcheon¹³⁵, C. Whyte¹³⁵ & C. Almaden-Boyle¹³⁵

Lister Hospital, Stevenage, UK

N. Pattison¹³⁶ & C. Cruz¹³⁶

Bedford Hospital, Bedford, UK

A. Vochin¹³⁷, H. Kent¹³⁷, A. Thomas¹³⁷, S. Murdoch¹³⁷, B. David¹³⁷, M. Penacerrada¹³⁷, G. Lubimbi¹³⁷, V. Bastion¹³⁷, R. Wulandari¹³⁷, J. Valentine¹³⁷ & D. Clarke¹³⁷

Royal United Hospital, Bath, UK

A. Serrano-Ruiz¹³⁸, S. Hierons¹³⁸, L. Ramos¹³⁸, C. Demetriou¹³⁸, S. Mitchard¹³⁸ & K. White¹³⁸

Royal Bournemouth Hospital, Bournemouth, UK

N. White¹³⁹, S. Pitts¹³⁹, D. Branney¹³⁹ & J. Frankham¹³⁹

The Great Western Hospital, Swindon, UK

M. Watters¹⁴⁰, H. Langton¹⁴⁰ & R. Prout¹⁴⁰

Watford General Hospital, Watford, UK

V. Page¹⁴¹ & T. Varghes¹⁴¹

University Hospital North Durham, Darlington, UK

A. Cowton¹⁴², A. Kay¹⁴², K. Potts¹⁴², M. Birt¹⁴², M. Kent¹⁴² & A. Wilkinson¹⁴²

Tameside General Hospital, Ashton Under Lyne, UK

E. Jude¹⁴³, V. Turner¹⁴³, H. Savill¹⁴³, J. McCormick¹⁴³, M. Clark¹⁴³, M. Coulding¹⁴³, S. Siddiqui¹⁴³, O. Mercer¹⁴³, H. Rehman¹⁴³ & D. Potla¹⁴³

Princess Royal Hospital, Telford and Royal Shrewsbury Hospital, Shrewsbury, UK

N. Capps¹⁴⁴, D. Donaldson¹⁴⁴, J. Jones¹⁴⁴, H. Button¹⁴⁴, T. Martin¹⁴⁴, K. Hard¹⁴⁴, A. Agasou¹⁴⁴, L. Tonks¹⁴⁴, T. Arden¹⁴⁴, P. Boyle¹⁴⁴, M. Carnahan¹⁴⁴, J. Strickley¹⁴⁴, C. Adams¹⁴⁴, D. Childs¹⁴⁴, R. Rikunenko¹⁴⁴, M. Leigh¹⁴⁴, M. Breekes¹⁴⁴, R. Wilcox¹⁴⁴, A. Bowes¹⁴⁴, H. Tiveran¹⁴⁴,
F. Hurford¹⁴⁴, J. Summers¹⁴⁴, A. Carter¹⁴⁴, Y. Hussain¹⁴⁴, L. Ting¹⁴⁴, A. Javaid¹⁴⁴, N. Motherwell¹⁴⁴, H. Moore¹⁴⁴, H. Millward¹⁴⁴, S. Jose¹⁴⁴, N. Schunki¹⁴⁴, A. Noakes¹⁴⁴ & C. Clulow¹⁴⁴

Arrowe Park Hospital, Wirral, UK

G. Sadera¹⁴⁵, R. Jacob¹⁴⁵ & C. Jones¹⁴⁵

The Queen Elizabeth Hospital, King’s Lynn, UK

M. Blunt¹⁴⁶, Z. Coton¹⁴⁶, H. Curgenven¹⁴⁶, S. Mohamed Ally¹⁴⁶, K. Beaumont¹⁴⁶, M. Elsaadany¹⁴⁶, K. Fernandes¹⁴⁶, I. Ali Mohamed Ali¹⁴⁶, H. Rangarajan¹⁴⁶, V. Sarathy¹⁴⁶, S. Selvanayagam¹⁴⁶, D. Vedage¹⁴⁶ & M. White¹⁴⁶

Royal Blackburn Teaching Hospital, Blackburn, UK

M. Smith¹⁴⁷, N. Truman¹⁴⁷, S. Chukkambotla¹⁴⁷, S. Keith¹⁴⁷, J. Cockerill-Taylor¹⁴⁷, J. Ryan-Smith¹⁴⁷, R. Bolton¹⁴⁷, P. Springle¹⁴⁷, J. Dykes¹⁴⁷, J. Thomas¹⁴⁷, M. Khan¹⁴⁷, M. T. Hijazi¹⁴⁷, E. Massey¹⁴⁷ & G. Croston¹⁴⁷

Poole Hospital, Poole, UK

H. Reschreite r¹⁴⁸, J. Camsooksai¹⁴⁸, S. Patch¹⁴⁸, S. Jenkins¹⁴⁸, C. Humphrey¹⁴⁸, B. Wadams¹⁴⁸ & J. Camsooksai¹⁴⁸

Medway Maritime Hospital, Gillingham, UK

N. Bhatia¹⁴⁹, M. Msiska¹⁴⁹ & O. Adanini¹⁴⁹

Warwick Hospital, Warwick, UK

B. Attwood¹⁵⁰ & P. Parsons¹⁵⁰

The Royal Marsden Hospital, London, UK

K. Tatham¹⁵¹, S. Jhanji¹⁵¹, E. Black¹⁵¹, A. Dela Rosa¹⁵¹, R. Howle¹⁵¹, B. Thomas¹⁵¹, T. Bemand¹⁵¹ & R. Raobaikady¹⁵¹

The Princess Alexandra Hospital, Harlow, UK

R. Saha¹⁵², N. Staines¹⁵², A. Daniel¹⁵² & J. Finn¹⁵²

Musgrove Park Hospital, Taunton, UK

J. Hutter¹⁵³, P. Doble¹⁵³, C. Shovelton¹⁵³ & C. Pawley¹⁵³

George Eliot Hospital NHS Trust, Nuneaton, UK

T. Kannan¹⁵⁴ & M. Hill¹⁵⁴

East Surrey Hospital, Redhill, UK

E. Combes¹⁵⁵, S. Monnery¹⁵⁵ & T. Joefield¹⁵⁵

West Middlesex Hospital, Isleworth, UK

M. Popescu¹⁵⁶, M. Thankachen¹⁵⁶ & M. Oblak¹⁵⁶

Warrington General Hospital, Warrington, UK

J. Little¹⁵⁷, S. McIvor¹⁵⁷, A. Brady¹⁵⁷, H. Whittle¹⁵⁷, H. Prady¹⁵⁷ & R. Chan¹⁵⁷

Southport and Formby District General Hospital, Ormskirk, UK

A. Ahmed¹⁵⁸ & A. Morris¹⁵⁸

Royal Devon and Exeter Hospital, Exeter, UK

C. Gibson¹⁵⁹, E. Gordon¹⁵⁹, S. Keenan¹⁵⁹, H. Quinn¹⁵⁹, S. Benyon¹⁵⁹, S. Marriott¹⁵⁹, L. Zitter¹⁵⁹, L. Park¹⁵⁹ & K. Baines¹⁵⁹

Macclesfield District General Hospital, Macclesfield, UK

M. Lyons¹⁶⁰, M. Holland¹⁶⁰, N. Keenan¹⁶⁰ & M. Young¹⁶⁰

Borders General Hospital, Melrose, UK

S. Garrioch¹⁶¹, J. Dawson¹⁶¹ & M. Tolson¹⁶¹

Birmingham Children’s Hospital, Birmingham, UK

B. Scholefield¹⁶² & R. Bi¹⁶²

William Harvey Hospital, Ashford, UK

N. Richardson¹⁶³, N. Schumacher¹⁶³, T. Cosier¹⁶³ & G. Millen¹⁶³

Royal Lancaster Infirmary, Lancaster, UK

A. Higham¹⁶⁴ & K. Simpson¹⁶⁴

Queen Elizabeth the Queen Mother Hospital, Margate, UK

S. Turki¹⁶⁵, L. Allen¹⁶⁵, N. Crisp¹⁶⁵, T. Hazleton¹⁶⁵, A. Knight¹⁶⁵, J. Deery¹⁶⁵, C. Price¹⁶⁵, S. Turney¹⁶⁵, S. Tilbey¹⁶⁵ & E. Beranova¹⁶⁵

Liverpool Heart and Chest Hospital, Liverpool, UK

D. Wright¹⁶⁶, L. Georg¹⁶⁶ & S. Twiss¹⁶⁶

Darlington Memorial Hospital, Darlington, UK

A. Cowton¹⁶⁷, S. Wadd¹⁶⁷ & K. Postlethwaite¹⁶⁷

Southend University Hospital, Westcliff-on-Sea, UK

P. Gondo¹⁶⁸, B. Masunda¹⁶⁸, A. Kayani¹⁶⁸ & B. Hadebe¹⁶⁸

Raigmore Hospital, Inverness, UK

J. Whiteside¹⁶⁹, R. Campbell¹⁶⁹ & N. Clarke¹⁶⁹

Salisbury District Hospital, Salisbury, UK

P. Donnison¹⁷⁰, F. Trim¹⁷⁰ & I. Leadbitter¹⁷⁰

Peterborough City Hospital, Peterborough, UK

D. Butcher¹⁷¹ & S. O’Sullivan¹⁷¹

Ipswich Hospital, Ipswich, UK

B. Purewal¹⁷², B. Purewal¹⁷², S. Bell¹⁷² & V. Rivers¹⁷²

Hereford County Hospital, Hereford, UK

R. O’Leary¹⁷³, J. Birch¹⁷³, E. Collins¹⁷³, S. Anderson¹⁷³, K. Hammerton¹⁷³ & E. Andrews¹⁷³

Furness General Hospital, Barrow-in-Furness, UK

A. Higham¹⁷⁴ & K. Burns¹⁷⁴

Forth Valley Royal Hospital, Falkirk, UK

I. Edmond¹⁷⁵, D. Salutous¹⁷⁵, A. Todd¹⁷⁵, J. Donnachie¹⁷⁵, P. Turner¹⁷⁵, L. Prentice¹⁷⁵, L. Symon¹⁷⁵, N. Runciman¹⁷⁵ & F. Auld¹⁷⁵

Torbay Hospital, Torquay, UK

M. Halkes¹⁷⁶, P. Mercer¹⁷⁶ & L. Thornton¹⁷⁶

St Mary’s Hospital, Newport, UK

G. Debreceni¹⁷⁷, J. Wilkins¹⁷⁷, A. Brown¹⁷⁷ & V. Crickmore¹⁷⁷

Royal Manchester Children’s Hospital, Manchester, UK

G. Subramanian¹⁷⁸, R. Marshall¹⁷⁸, C. Jennings¹⁷⁸, M. Latif¹⁷⁸ & L. Bunni¹⁷⁸

Royal Cornwall Hospital, Truro, UK

M. Spivey¹⁷⁹, S. Bean¹⁷⁹ & K. Burt¹⁷⁹

Queen Elizabeth Hospital Gateshead, Gateshead, UK

V. Linnett¹⁸⁰, J. Ritzema¹⁸⁰, A. Sanderson¹⁸⁰, W. McCormick¹⁸⁰ & M. Bokhari¹⁸⁰

Kent & Canterbury Hospital, Canterbury, UK

R. Kapoor¹⁸¹ & D. Loader¹⁸¹

James Paget University Hospital NHS Trust, Great Yarmouth, UK

A. Ayers¹⁸², W. Harrison¹⁸² & J. North¹⁸²

Darent Valley Hospital, Dartford, UK

Z. Belagodu¹⁸³, R. Parasomthy¹⁸³, O. Olufuwa¹⁸³, A. Gherman¹⁸³, B. Fuller¹⁸³ & C. Stuart¹⁸³

The Alexandra Hospital, Redditch and Worcester Royal Hospital, Worcester, UK

O. Kelsall¹⁸⁴, C. Davis¹⁸⁴, L. Wild¹⁸⁴, H. Wood¹⁸⁴, J. Thrush¹⁸⁴, A. Durie¹⁸⁴, K. Austin¹⁸⁴, K. Archer¹⁸⁴, P. Anderson¹⁸⁴ & C. Vigurs¹⁸⁴

Ysbyty Gwynedd, Bangor, UK

C. Thorpe¹⁸⁵, A. Thomas¹⁸⁵, E. Knights¹⁸⁵, N. Boyle¹⁸⁵ & A. Price¹⁸⁵

Yeovil Hospital, Yeovil, UK

A. Kubisz-Pudelko¹⁸⁶, D. Wood¹⁸⁶, A. Lewis¹⁸⁶, S. Board¹⁸⁶, L. Pippard¹⁸⁶, J. Perry¹⁸⁶ & K. Beesley¹⁸⁶

University Hospital Hairmyres, East Kilbride, UK

A. Rattray¹⁸⁷, M. Taylor¹⁸⁷, E. Lee¹⁸⁷, L. Lennon¹⁸⁷, K. Douglas¹⁸⁷, D. Bell¹⁸⁷, R. Boyle¹⁸⁷ & L. Glass¹⁸⁷

Scunthorpe General Hospital, Scunthorpe, UK

M. Nauman Akhtar¹⁸⁸, K. Dent¹⁸⁸, D. Potoczna¹⁸⁸, S. Pearson¹⁸⁸, E. Horsley¹⁸⁸ & S. Spencer¹⁸⁸

Princess Royal Hospital Brighton, West Sussex, UK

C. Phillips¹⁸⁹, D. Mullan¹⁸⁹, D. Skinner¹⁸⁹, J. Gaylard¹⁸⁹ & L. Ortiz-Ruizdegordoa¹⁸⁹

Lincoln County Hospital, Lincoln, UK

R. Barber¹⁹⁰, C. Hewitt¹⁹⁰, A. Hilldrith¹⁹⁰, S. Shepardson¹⁹⁰, M. Wills¹⁹⁰ &
K. Jackson-Lawrence¹⁹⁰

Homerton University Hospital, London, UK

A. Gupta¹⁹¹, A. Easthope¹⁹¹, E. Timlick¹⁹¹ & C. Gorman¹⁹¹

Glangwili General Hospital, Camarthen, UK

I. Otaha¹⁹², A. Gales¹⁹², S. Coetzee¹⁹², M. Raj¹⁹² & M. Peiu¹⁹²

Ealing Hospital, Southall, UK

V. Parris¹⁹³, S. Quaid¹⁹³ & E. Watson¹⁹³

Scarborough General Hospital, Scarborough, UK

K. Elliott¹⁹⁴, J. Mallinson¹⁹⁴, B. Chandler¹⁹⁴ & A. Turnbull¹⁹⁴

Royal Albert Edward Infirmary, Wigan, UK

A. Quinn¹⁹⁵, C. Finch¹⁹⁵, C. Holl¹⁹⁵, J. Cooper¹⁹⁵ & A. Evans¹⁹⁵

Queen Elizabeth Hospital, Woolwich, London, UK

W. Khaliq¹⁹⁶, A. Collins¹⁹⁶ & E. Treus Gude¹⁹⁶

North Devon District Hospital, Barnstaple, UK

N. Love¹⁹⁷, L. van Koutrik¹⁹⁷, J. Hunt¹⁹⁷, D. Kaye¹⁹⁷, E. Fisher¹⁹⁷, A. Brayne¹⁹⁷, V. Tuckey¹⁹⁷, P. Jackson¹⁹⁷ & J. Parkin¹⁹⁷

National Hospital for Neurology and Neurosurgery, London, UK

D. Brealey¹⁹⁸, E. Raith¹⁹⁸, A. Tariq¹⁹⁸, H. Houlden¹⁹⁸, A. Tucci¹⁹⁸, J. Hardy¹⁹⁸ & E. Moncur¹⁹⁸

Eastbourne District General Hospital, East Sussex, UK and Conquest Hospital, East Sussex, UK

J. Highgate¹⁹⁹ & A. Cowley¹⁹⁹

Diana Princess of Wales Hospital, Grimsby, UK

A. Mitra²⁰⁰, R. Stead²⁰⁰, T. Behan²⁰⁰, C. Burnett²⁰⁰, M. Newton²⁰⁰, E. Heeney²⁰⁰, R. Pollard²⁰⁰ & J. Hatton²⁰⁰

The Christie NHS Foundation Trust, Manchester, UK

A. Patel²⁰¹, V. Kasipandian²⁰¹, S. Allibone²⁰¹ & R. M. Genetu²⁰¹

Prince Philip Hospital, Lianelli, UK

I. Otahal²⁰², L. O’Brien²⁰², Z. Omar²⁰², E. Perkins²⁰² & K. Davies²⁰²

Prince Charles Hospital, Merthyr Tydfil, UK

D. Tetla²⁰³, C. Pothecary²⁰³ & B. Deacon²⁰³

Golden Jubilee National Hospital, Clydebank, UK

B. Shelley²⁰⁴ & V. Irvine²⁰⁴

Dorset County Hospital, Dorchester, UK

S. Williams²⁰⁵, P. Williams²⁰⁵, J. Birch²⁰⁵, J. Goodsell²⁰⁵, R. Tutton²⁰⁵, L. Bough²⁰⁵ & B. Winter-Goodwin²⁰⁵

Calderdale Royal Hospital, Halifax, UK

R. Kitson²⁰⁶, J. Pinnell²⁰⁶, A. Wilson²⁰⁶, T. Nortcliffe²⁰⁶, T. Wood²⁰⁶, M. Home²⁰⁶, K. Holdroyd²⁰⁶, M. Robinson²⁰⁶, K. Hanson²⁰⁶, R. Shaw²⁰⁶, J. Greig²⁰⁶, M. Brady²⁰⁶, A. Haigh²⁰⁶, L. Matupe²⁰⁶, M. Usher²⁰⁶, S. Mellor²⁰⁶, S. Dale²⁰⁶, L. Gledhill²⁰⁶, L. Shaw²⁰⁶, G. Turner²⁰⁶, D. Kelly²⁰⁶, B. Anwar²⁰⁶, H. Riley²⁰⁶, H. Sturgeon²⁰⁶, A. Ali²⁰⁶, L. Thomis²⁰⁶, D. Melia²⁰⁶,
A. Dance²⁰⁶ & K. Hanson²⁰⁶

West Suffolk Hospital, Suffolk, UK

S. Humphreys²⁰⁷, I. Frost²⁰⁷, V. Gopal²⁰⁷, J. Godden²⁰⁷, A. Holden²⁰⁷ & S. Swann²⁰⁷

West Cumberland Hospital, Whitehaven, UK

T. Smith²⁰⁸, M. Clapham²⁰⁸, U. Poultney²⁰⁸, R. Harper²⁰⁸ & P. Rice²⁰⁸

University Hospital Lewisham, London, UK

W. Khaliq²⁰⁹, R. Reece-Anthony²⁰⁹ & B. Gurung²⁰⁹

St John’s Hospital Livingston, Livingston, UK

S. Moultrie²¹⁰ & M. Odam²¹⁰

Sheffield Children’s Hospital, Sheffield, UK

A. Mayer²¹¹, A. Bellini²¹¹, A. Pickard²¹¹, J. Bryant²¹¹, N. Roe²¹¹ & J. Sowter²¹¹

Hinchingbrooke Hospital, Huntingdon, UK

D. Butcher²¹², K. Lang²¹² & J. Taylor²¹²

Glenfield Hospital, Leicester, UK

P. Barry²¹³

Bronglais General Hospital, Aberystwyth, UK

M. Hobrok²¹⁴, H. Tench²¹⁴, R. Wolf-Roberts²¹⁴, H. McGuinness²¹⁴ & R. Loosley²¹⁴

Alder Hey Children’s Hospital, Liverpool, UK

D. Hawcutt²¹⁵, L. Rad²¹⁵, L. O’Malley²¹⁵, P. Saunderson²¹⁵, G. Seddon²¹⁵, T. Anderson²¹⁵ & N. Rogers²¹⁵

University Hospital Monklands, Airdrie, UK

J. Ruddy²¹⁶, H. Margaret²¹⁶, M. Taylor²¹⁶, C. Beith²¹⁶, A. McAlpine²¹⁶, L. Ferguson²¹⁶, P. Grant²¹⁶, S. MacFadyen²¹⁶, M. McLaughlin²¹⁶, T. Baird²¹⁶, S. Rundell²¹⁶, L. Glass²¹⁶, B. Welsh²¹⁶, R. Hamill²¹⁶ & F. Fisher²¹⁶

Cumberland Infirmary, Carlisle, UK

T. Smith²¹⁷, J. Gregory²¹⁷ & A. Brown²¹⁷

³⁹Barts Health NHS Trust, London, UK. ⁴⁰Guys and St Thomas’ Hospital, London, UK. ⁴¹James Cook University Hospital, Middlesburgh, UK. ⁴²The Royal Liverpool University Hospital, Liverpool, UK. ⁴³King’s College Hospital, London, UK. ⁴⁴Royal Infirmary of Edinburgh, Edinburgh, UK. ⁴⁵John Radcliffe Hospital, Oxford, UK. ⁴⁶Addenbrooke’s Hospital, Cambridge, UK. ⁴⁷Morriston Hospital, Swansea, UK. ⁴⁸Ashford and St Peter’s Hospital, Chertsey, UK. ⁴⁹Royal Stoke University Hospital, Stoke-on-Trent, UK. ⁵⁰Queen Elizabeth Hospital, Birmingham, UK. ⁵¹Glasgow Royal Infirmary, Glasgow, UK. ⁵²Kingston Hospital, Kingston upon Thames, UK. ⁵³The Tunbridge Wells Hospital and Maidstone Hospital, Maidstone, UK. ⁵⁴North Middlesex University Hospital NHS Trust, London, UK. ⁵⁵Bradford Royal Infirmary, Bradford, UK. ⁵⁶Blackpool Victoria Hospital, Blackpool, UK. ⁵⁷Countess of Chester Hospital, Chester, UK. ⁵⁸Wythenshawe Hospital, Manchester, UK. ⁵⁹St George’s Hospital, London, UK. ⁶⁰Good Hope Hospital, Birmingham, UK. ⁶¹Stepping Hill Hospital, Stockport, UK. ⁶²Manchester Royal Infirmary, Manchester, UK. ⁶³Royal Alexandra Hospital, Paisley, UK. ⁶⁴Queen Elizabeth University Hospital, Glasgow, UK. ⁶⁵Queen Alexandra Hospital, Portsmouth, UK. ⁶⁶BHRUT (Barking Havering) - Queens Hospital and King George Hospital, Ilford, UK. ⁶⁷University College Hospital, London, UK. ⁶⁸Royal Victoria Infirmary, Newcastle Upon Tyne, UK. ⁶⁹Western Sussex Hospitals, Chichester, UK. ⁷⁰Salford Royal Hospital, Manchester, UK. ⁷¹The Royal Oldham Hospital, Manchester, UK. ⁷²Pinderfields General Hospital, Wakefield, UK. ⁷³Basildon Hospital, Basildon, UK. ⁷⁴University Hospital of Wales, Cardiff, UK. ⁷⁵Broomfield Hospital, Chelmsford, UK. ⁷⁶Royal Brompton Hospital, London, UK. ⁷⁷Nottingham University Hosp tal, Nottingham, UK. ⁷⁸Royal Hallamshire Hospital and Northern General Hospital, Sheffield, UK. ⁷⁹Royal Hampshire County Hospital, Winchester, UK. ⁸⁰Queens Hospital Burton, Burton-On-Trent, UK. ⁸¹New Cross Hospital, Wolverhampton, UK. ⁸²Heartlands Hospital, Birmingham, UK. ⁸³Walsall Manor Hospital, Walsall, UK. ⁸⁴Stoke Mandeville Hospital, Aylesbury, UK. ⁸⁵Sandwell General Hospital, Birmingham, UK. ⁸⁶Royal Berkshire NHS Foundation Trust, Reading, UK. ⁸⁷Charing Cross Hospital, St Mary’s Hospital and Hammersmith Hospital, London, UK. ⁸⁸Dumfries and Galloway Royal Infirmary, Dumfries, UK. ⁸⁹Bristol Royal Infirmary, Bristol, UK. ⁹⁰Royal Sussex County Hospital, Brighton, UK. ⁹¹Whiston Hospital, Prescot, UK. ⁹²Royal Glamorgan Hospital, Cardiff, UK. ⁹³King’s Mill Hospital, Nottingham, UK. ⁹⁴Fairfield General Hospital, Bury, UK. ⁹⁵Western General Hospital, Edinburgh, UK. ⁹⁶Northwick Park Hospital, London, UK. ⁹⁷Royal Preston Hospital, Preston, UK. ⁹⁸Royal Derby Hospital, Derby, UK. ⁹⁹Sunderland Royal Hospital, Sunderland, UK. ¹⁰⁰Royal Surrey County Hospital, Guildford, UK. ¹⁰¹Derriford Hospital, Plymouth, UK. ¹⁰²Croydon University Hospital, Croydon, UK. ¹⁰³Victoria Hospital, Kirkcaldy, UK. ¹⁰⁴Milton Keynes University Hospital, Milton Keynes, UK. ¹⁰⁵Barnsley Hospital, Barnsley, UK. ¹⁰⁶York Hospital, York, UK. ¹⁰⁷University Hospital of North Tees, Stockton on Tees, UK. ¹⁰⁸University Hospital Wishaw, Wishaw, UK. ¹⁰⁹Whittington Hospital, London, UK. ¹¹⁰Southmead Hospital, Bristol, UK. ¹¹¹The Royal Papworth Hospital, Cambridge, UK. ¹¹²Royal Gwent Hospital, Newport, UK. ¹¹³Norfolk and Norwich University Hospital (NNUH), Norwich, UK. ¹¹⁴Great Ormond St Hospital and UCL Great Ormond St Institute of Child Health NIHR Biomedical Research Centre, London, UK. ¹¹⁵Airedale General Hospital, Keighley, UK. ¹¹⁶Aberdeen Royal Infirmary, Aberdeen, UK. ¹¹⁷Southampton General Hospital, Southampton, UK. ¹¹⁸Russell’s Hall Hospital, Dudley, UK. ¹¹⁹Rotherham General Hospital, Rotherham, UK. ¹²⁰North Manchester General Hospital, Manchester, UK. ¹²¹Basingstoke and North Hampshire Hospital, Basingstoke, UK. ¹²²Royal Free Hospital, London, UK. ¹²³Hull Royal Infirmary, Hull, UK. ¹²⁴Harefield Hospital, London, UK. ¹²⁵Chesterfield Royal Hospital Foundation Trust, Chesterfield, UK. ¹²⁶Barnet Hospital, London, UK. ¹²⁷Aintree University Hospital, Liverpool, UK. ¹²⁸St James’s University Hospital and Leeds General Infirmary, Leeds, UK. ¹²⁹Glan Clwyd Hospital, Bodelwyddan, UK. ¹³⁰University Hospital Crosshouse, Kilmarnock, UK. ¹³¹Royal Bolton Hospital, Bolton, UK. ¹³²Princess of Wales Hospital, Llantrisant, UK. ¹³³Pilgrim Hospital, Lincoln, UK. ¹³⁴Northumbria Healthcare NHS Foundation Trust, North Shields, UK. ¹³⁵Ninewells Hospital, Dundee, UK. ¹³⁶Lister Hospital, Stevenage, UK. ¹³⁷Bedford Hospital, Bedford, UK. ¹³⁸Royal United Hospital, Bath, UK. ¹³⁹Royal Bournemouth Hospital, Bournemouth, UK. ¹⁴⁰The Great Western Hospital, Swindon, UK. ¹⁴¹Watford General Hospital, Watford, UK. ¹⁴²University Hospital North Durham, Darlington, UK. ¹⁴³Tameside General Hospital, Ashton Under Lyne, UK. ¹⁴⁴Princess Royal Hospital Shrewsbury and Royal Shrewsbury Hospital, Shrewsbury, UK. ¹⁴⁵Arrowe Park Hospital, Wirral, UK. ¹⁴⁶The Queen Elizabeth Hospital, King’s Lynn, UK. ¹⁴⁷Royal Blackburn Teaching Hospital, Blackburn, UK. ¹⁴⁸Poole Hospital, Poole, UK. ¹⁴⁹Medway Maritime Hospital, Gillingham, UK. ¹⁵⁰Warwick Hospital, Warwick, UK. ¹⁵¹The Royal Marsden Hospital, London, UK. ¹⁵²The Princess Alexandra Hospital, Harlow, UK. ¹⁵³Musgrove Park Hospital, Taunton, UK. ¹⁵⁴George Eliot Hospital NHS Trust, Nuneaton, UK. ¹⁵⁵East Surrey Hospital, Redhill, UK. ¹⁵⁶West Middlesex Hospital, Isleworth, UK. ¹⁵⁷Warrington General Hospital, Warrington, UK. ¹⁵⁸Southport and Formby District General Hospital, Ormskirk, UK. ¹⁵⁹Royal Devon and Exeter Hospital, Exeter, UK. ¹⁶⁰Macclesfield District General Hospital, Macclesfield, UK. ¹⁶¹Borders General Hospital, Melrose, UK. ¹⁶²Birmingham Children’s Hospital, Birmingham, UK. ¹⁶³William Harvey Hospital, Ashford, UK. ¹⁶⁴Royal Lancaster Infirmary, Lancaster, UK. ¹⁶⁵Queen Elizabeth the Queen Mother Hospital, Margate, UK. ¹⁶⁶Liverpool Heart and Chest Hospital, Liverpool, UK. ¹⁶⁷Darlington Memorial Hospital, Darlington, UK. ¹⁶⁸Southend University Hospital, Westcliffon- Sea, UK. ¹⁶⁹Raigmore Hospital, Inverness, UK. ¹⁷⁰Salisbury District Hospital, Salisbury, UK. ¹⁷¹Peterborough City Hospital, Peterborough, UK. ¹⁷²Ipswich Hospital, Ipswich, UK. ¹⁷³Hereford County Hospital, Worcester, UK. ¹⁷⁴Furness General Hospital, Barrow-in-Furness, UK. ¹⁷⁵Forth Valley Royal Hospital, Falkirk, UK. ¹⁷⁶Torbay Hospital, Torquay, UK. ¹⁷⁷St Mary’s Hospital, Newport, UK. ¹⁷⁸Royal Manchester Children’s Hospital, Manchester, UK. ¹⁷⁹Royal Cornwall Hospital, Truro, UK. ¹⁸⁰Queen Elizabeth Hospital Gateshead, Gateshead, UK. ¹⁸¹Kent & Canterbury Hospital, Canterbury, UK. ¹⁸²James Paget University Hospital NHS Trust, Great Yarmouth, UK. ¹⁸³Darent Valley Hospital, Dartford, UK. ¹⁸⁴The Alexandra Hospital, Redditch and Worcester Royal Hospital, Worcester, UK. ¹⁸⁵Ysbyty Gwynedd, Bangor, UK. ¹⁸⁶Yeovil Hospital, Yeovil, UK. ¹⁸⁷University Hospital Hairmyres, East Kilbride, UK. ¹⁸⁸Scunthorpe General Hospital, Scunthorpe, UK. ¹⁸⁹Princess Royal Hospital Brighton, Haywards Heath, UK. ¹⁹⁰Lincoln County Hospital, Lincoln, UK. ¹⁹¹Homerton University Hospital, London, UK. ¹⁹²Glangwili General Hospital, Camarthen, UK. ¹⁹³Ealing Hospital, London, UK. ¹⁹⁴Scarborough General Hospital, Scarborough, UK. ¹⁹⁵Royal Albert Edward Infirmary, Wigan, UK. ¹⁹⁶Queen Elizabeth Hospital, Woolwich, London, UK. ¹⁹⁷North Devon District Hospital, Barnstaple, UK. ¹⁹⁸National Hospital for Neurology a d Neurosurgery, London, UK. ¹⁹⁹Eastbourne District General Hospital, East Sussex, UK and Conquest Hospital, Eastbourne, UK. 200Diana Princess of Wales Hospital, Grimsby, UK. ²⁰¹The Christie NHS Foundation Trust, Manchester, UK. ²⁰²Prince Philip Hospital, Lianelli, UK. ²⁰³Prince Charles Hospital, Merthyr Tydfil, UK. ²⁰⁴Golden Jubilee National Hospital, Clydebank, UK. ²⁰⁵Dorset County Hospital, Dorchester, UK. ²⁰⁶Calderdale Royal Hospital, Halifax, UK. ²⁰⁷West Suffolk Hospital, Bury St Edmunds, UK. ²⁰⁸West Cumberland Hospital, Whitehaven, UK. ²⁰⁹University Hospital Lewisham, London, UK. ²¹⁰St John’s Hospital Livingston, Livingston, UK. ²¹¹Sheffield Children’s Hospital, Sheffield, UK. ²¹²Hinchingbrooke Hospital, Huntingdon, UK. ²¹³Glenfield Hospital, Leicester, UK. ²¹⁴Bronglais General Hospital, Aberystwyth, UK. ²¹⁵Alder Hey Children’s Hospital, Liverpool, UK. ²¹⁶University Hospital Monklands, Airdrie, UK. ²¹⁷Cumberland Infirmary, Carlisle, UK.

The list of members and their affiliations can be found in the supplementary information.

ISARIC4C Consortium

ISARICC Collaborators

J. Kenneth Baillie^1,2,11, Malcolm G. Semple^18,38, Peter J. M. Openshaw^36,37, Gail Carson²⁸⁶, Beatrice Alex²⁸⁷, Benjamin Bach²⁸⁷, Wendy S. Barclay²⁸⁸, Debby Bogaert⁴, Meera Chand²⁸⁹, Graham S. Cooke²⁹⁰, Annemarie B. Docherty^11,291, Jake Dunning^36,292, Ana da Silva Filipe²⁹³, Tom Fletcher²⁹⁴, Christoper A. Green²⁹⁵, Ewen M. Harrison²⁹¹, Julian A. Hiscox²⁹⁶, Antonia Ying Wai Ho^293,297, Peter W. Horby²¹, Samreen Ijaz²⁹⁸, Saye Khoo²⁹⁹, Paul Klenerman^300,301, Andrew Law^{1, Wei Shen Lim77, Alexander J. Mentzer300,302, Laura Merson286, Alison M. Meynert2, Mahdad Noursadeghi303, Shona C. Moore304, Massimo Palmarini293, William A. Paxton304,305, Georgios Pollakis304,305, Nicholas Price306,307, Andrew Rambaut308, David L. Robertson293, Clark D. Russell1,4, Vanessa Sancho-Shimizu309, Janet T. Scott293,310, Thushan de Silva311, Louise Sigfrid286, Tom Solomon18,312,}Shiranee Sriskandan^290,313, David Stuart³¹⁴, Charlotte Summers¹⁵, Richard S. Tedder^315,316,317, Emma C. Thomson²⁹³, AA Roger Thompson³¹⁸, Ryan S. Thwaites36, Lance CW Turtle^18,319 & Maria Zambon²⁹² Project management team

Hayley Hardwick¹⁸, Chloe Donohue320, Ruth Lyons¹, Fiona Griffiths¹ & Wilna Oosthuyzen¹

Data Analysis Team

Lisa Norman²⁹¹, Riinu Pius²⁹¹, Thomas M. Drake²⁹¹, Cameron J. Fairfield²⁹¹, Stephen R. Knight²⁹¹, Kenneth A. Mclean²⁹¹, Derek Murphy²⁹¹ & Catherine A. Shaw²⁹¹

Data Architecture Team

Jo Dalton³²⁰, Michelle Girvan³²⁰, Egle Saviciute³²⁰, Stephanie Roberts³²⁰, Janet Harrison³²⁰, Laura Marsh³²⁰, Marie Connor³²⁰, Sophie Halpin³²⁰, Clare Jackson³²⁰, Carrol Gamble³²⁰, Gary Leeming³²¹, Andrew Law¹, Murray Wham², Sara Clohisey¹, Ross Hendry¹ & James Scott-Brown²⁸⁷

Data Analytics and Management Team

William Greenhalf³²², Victoria Shaw³²³, Sara McDonald²⁹³ & Seán Keating¹¹

²⁸⁶ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. ²⁸⁷School of Informatics, University of Edinburgh, Edinburgh, UK. ²⁸⁸Section of Molecular Virology, Imperial College London, London, UK. ²⁸⁹Antimicrobial Resistance and Hospital Acquired Infection Department, Public Health England, London, UK. ²⁹⁰Department of Infectious Disease, Imperial College London, London, UK. ²⁹¹Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK. ²⁹²National Infection Service, Public Health England, London, UK. ²⁹³MRC-University of Glasgow Centre for Virus Research, ⁴⁶⁴ Bearsden Road, Glasgow, UK. ²⁹⁴Liverpool School of Tropical Medicine, Liverpool, UK. ²⁹⁵Institute of M crobiology and Infection, University of Birmingham, Birmingham, UK. ²⁹⁶Institute of Infection and Global Health, University of Liverpool, Liverpool, UK. ²⁹⁷Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK. ²⁹⁸Virology Reference Department, National Infection Service, Public Health England, Colindale Avenue, London, UK. ²⁹⁹Department of Pharmacology, University of Liverpool, Liverpool, UK. ³⁰⁰Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK. ³⁰¹Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK. ³⁰²Department of Microbiology/Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. ³⁰³Division of Infection and Immunity, University College London, UK. ³⁰⁴Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. ³⁰⁵NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK. ³⁰⁶Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK. ³⁰⁷Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. ³⁰⁸Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK. ³⁰⁹Department of Pediatrics and Virology, St Mary’s Medical School Bldg, Imperial College London, London, UK. ³¹⁰NHS Greater Glasgow & Clyde, Glasgow, UK. ³¹¹The Florey Institute for Host-Pathogen Interactions, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. ³¹²Walton Centre NHS Foundation Trust, Liverpool, UK. ³¹³MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK. ³¹⁴Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford, Headington, Oxford, OX^{3 7}BN, UK. ³¹⁵Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK. ³¹⁶Transfusion Microbiology, National Health Service Blood and Transplant, London, UK ³¹⁷Department of Medicine, Imperial College London, London, UK. ³¹⁸Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. ³¹⁹Tropical & Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK. ³²⁰Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK. ³²¹Centre for Health Informatics, Division of Informatics, Imaging and Data Science, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. ³²²Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. ³²³Institute of Translational Medicine, University of Liverpool, Liverpool, Merseyside, UK.

The list of members and their affiliations can be found in the supplementary information.

HGI Consortium (Covid-19 Host Genetics Initiative)

Andrea Ganna^218,219, Patrick Sulem²²⁰, David A. van Heel²²¹, Mattia Cordioli²¹⁸, Alessandra Renieri^31,32, Gardar Sveinbjornsson²²⁰, Mari E. K. Niemi²¹⁸ & Alex Pereira²²²

²¹⁸Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. ²¹⁹Analytic & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ²²⁰deCODE genetics/Amgen, Inc., Sturlugata 8, 101 Reykjavik, Iceland. ²²¹Blizard Institute, Queen Mary University of London, 4 Newark Street, London, UK. ²²²Heart Institute, University of Sao Paulo, Brazil.

The list of members and their affiliations can be found in the supplementary information.

23andMe Contributors

Janie F. Shelton²²³, Anjali J. Shastri²²³, Chelsea Ye²²³, Catherine H. Weldon²²³, Teresa Filshtein-Sonmez²²³, Daniella Coker²²³, Antony Symons²²³ , Jorge Esparza-Gordillo²²⁴, The ^23andMe COVID-19 Team²²³, Stella Aslibekyan²²³ & Adam Auton²²³

²²³23andMe Inc., ²²³ N Mathilda Ave, Sunnyvale, CA, 94086, USA. ²²⁴Human genetics - R&D, GSK Medicines Research Centre, Target Sciences-R&D, Stevenage, UK.

The list of members and their affiliations can be found in the supplementary information.

GEN-COVID Contributors

Francesca Mari^31,32, Sergio Daga³¹, Margherita Baldassarri³¹, Elisa Benetti²²⁵, Simone Furini²²⁵, Chiara Fallerini³¹, Francesca Fava^31,32, Floriana Valentino³¹, Gabriella Doddato³¹, Annarita Giliberti³¹, Rossella Tita³², Sara Amitrano³², Mirella Bruttini^31,32, Susanna Croci³¹, Ilaria Meloni³¹, Anna Maria Pinto³², Elisa Frullanti³¹, Ilaria Meloni³¹, Caterina Lo Rizzo³², Francesca Montagnani²²⁶, Laura Di Sarno³¹, Andrea Tommasi^31,32, Maria Palmieri³¹, Arianna Emiliozzi²²⁶, Massimiliano Fabbiani²²⁶, Barbara Rossetti²²⁶, Giacomo Zanelli²²⁶, Elena Bargagli²²⁷, Laura Bergantini²²⁷, Miriana D’Alessandro²²⁷, Paolo Cameli²²⁷, David Bennet²²⁷, Federico Anedda²²⁸, Simona Marcantonio²²⁸, Sabino Scolletta²²⁸, Federico Franchi²²⁸, Maria Antonietta Mazzei²²⁹, Susanna Guerrini²²⁹, Edoardo Conticini²³⁰, Luca Cantarini²³⁰, Bruno Frediani²³⁰, Danilo Tacconi²³¹, Chiara Spertilli²³¹, Marco Feri²³², Alice Donati²³², Raffaele Scala²³³, Luca Guidelli²³³, Genni Spargi²³⁴, Marta Corridi²³⁴, Cesira Nencioni²³⁵, Leonardo Croci²³⁵, Gian Piero Caldarelli²³⁶, Maurizio Spagnesi²³⁷, Paolo Piacentini²³⁷, Maria Bandini²³⁷, Elena Desanctis²³⁷, Silvia Cappelli²³⁷, Anna Canaccini²³⁸, Agnese Verzuri²³⁸, Valentina Anemoli²³⁸, Antonella D’Arminio Monforte²³⁹, Esther Merlini²³⁹, Mario U. Mondelli²⁴⁰,²⁴¹, Stefania Mantovani²⁴⁰, Serena Ludovisi²⁴⁰,²⁴¹, Massimo Girardis²⁴², Sophie Venturelli²⁴², Marco Sita²⁴², Andrea Antinori²⁴³, Alessandra Vergori²⁴³, Stefano Rusconi^244,245, Matteo Siano²⁴⁵, Arianna Gabrieli²⁴⁵, Agostino Riva²⁴⁴,²⁴⁵, Daniela Francisci²⁴⁶, Elisabetta Schiaroli²⁴⁶, Pier Giorgio Scotton²⁴⁷, Francesca Andretta²⁴⁷, Sandro Panese²⁴⁸, Renzo Scaggiante²⁴⁹, Francesca Gatti²⁴⁹, Saverio Giuseppe Parisi²⁵⁰, Francesco Castelli²⁵¹, Maria Eugenia Quiros-Roldan²⁵¹, Paola Magro²⁵¹, Isabella Zanella²⁵², Matteo Della Monica²⁵³, Carmelo Piscopo²⁵³, Mario Capasso^254,255,256, Roberta Russo^254,255, Immacolata Andolfo^254,255, Achille Iolascon^254,255, Giuseppe Fiorentino²⁵⁷, Massimo Carella²⁵⁸, Marco Castori²⁵⁸, Giuseppe Merla²⁵⁸, Filippo Aucella²⁵⁹, Pamela Raggi²⁶⁰, Carmen Marciano²⁶⁰, Rita Perna²⁶⁰, Matteo Bassetti^261,262, Antonio Di Biagio²⁶², Maurizio Sanguinetti^263,264, Luca Masucci^263,264, Serafina Valente²⁶⁵, Marco Mandalà²⁶⁶, Alessia Giorli²⁶⁶, Lorenzo Salerni²⁶⁶, Patrizia Zucchi²⁶⁷, Pierpaolo Parravicini²⁶⁷, Elisabetta Menatti²⁶⁸, Stefano Baratti²⁶⁹, Tullio Trotta²⁷⁰, Ferdinando Giannattasio²⁷⁰, Gabriella Coiro²⁷⁰, Fabio Lena²⁷¹, Domenico A. Coviello²⁷², Cristina Mussini²⁷³, Giancarlo Bosio²⁷⁴, Enrico Martinelli²⁷⁴, Sandro Mancarella²⁷⁵, Luisa Tavecchia²⁷⁵, Lia Crotti^276,277, Nicola Picchiotti^278,279, Marco Gori^278,280, Chiara Gabbi²⁸¹, Maurizio Sanarico²⁸², Stefano Ceri²⁸³, Pietro Pinoli²⁸³, Francesco Raimondi²⁸⁴, Filippo Biscarini^285,324 & Alessandra Stella^285,323

²²⁵Department of Medical Biotechnologies, University of Siena, Siena, Italy. ²²⁶Dept of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, University Hospital of Siena, Siena, Italy. ²²⁷Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy. ²²⁸Dept of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy. ²²⁹Department of Medical, Surgical and Neurosciences and Radiological Sciences, Unit of Diagnostic Imaging, University of Siena, Siena, Italy. ²³⁰Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy. ²³¹Department of Specialized and Internal Medicine, Infectious Diseases Unit, San Donato Hospital Arezzo, Arezzo, Italy. ²³²Dept of Emergency, Anesthesia Unit, San Donato Hospital, Arezzo, Italy. ²³³Department of Specialized and Internal Medicine, Pneumology Unit and UTIP, San Donato Hospital, Arezzo, Italy. ²³⁴Department of Emergency, Anesthesia Unit, Misericordia Hospital, Grosseto, Italy. ²³⁵Department of Specialized and Internal Medicine, Infectious Diseases Unit, Misericordia Hospital, Grosseto, Italy. ²³⁶Clinical Chemical Analysis Laboratory, Misericordia Hospital, Grosseto, Italy. ²³⁷Department of Preventive Medicine, Azienda USL Toscana Sud Est, Arezzo, Italy. ²³⁸Territorial Scientific Technician Department, Azienda USL Toscana Sud Est, Arezzo, Italy. ²³⁹Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy. ²⁴⁰Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. ²⁴¹Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. ²⁴²Department of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy. ²⁴³HIV/AIDS Department, National Institute for Infectious Diseases, IRCCS, Lazzaro Spallanzani, Rome, Italy. ²⁴⁴III Infectious Diseases Unit, ASST-FBF-Sacco, Milan, Italy. ²⁴⁵Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy. ²⁴⁶Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy. ²⁴⁷Department of Infectious Diseases, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy. ²⁴⁸Clinical Infectious Diseases, Mestre Hospital, Venice, Italy. ²⁴⁹Infectious Diseases Clinic, ULSS1, Belluno, Italy. ²⁵⁰Department of Molecular Medicine, University of Padova, Padua, Italy. ²⁵¹Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy. ²⁵²Department of Molecular and Translational Medicine, University of Brescia, Italy; Clinical Chemistry Laboratory, Cytogenetics and Molecular Genetics Section, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy. ²⁵³Medical Genetics and Laboratory of Medical Genetics Unit, A.O.R.N. “Antonio Cardarelli”, Naples, Italy. ²⁵⁴Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. ²⁵⁵CEINGE Biotecnologie Avanzate, Naples, Italy. ²⁵⁶IRCCS SDN, Naples, Italy. ²⁵⁷Unit of Respiratory Physiopathology, AORN dei Colli Monaldi Hospital, Naples, Italy. ²⁵⁸Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. ²⁵⁹Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. ²⁶⁰Clinical Trial Office, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. ²⁶¹Department of Health Sciences, University of Genova, Genoa, Italy. ²⁶²Infectious Diseases Clinic, Policlinico San Martino Hospital, IRCCS for Cancer Research Genoa, Genova, Italy. ²⁶³Microbiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Medicine, Rome, Italy. ²⁶⁴Department of Laboratory Sciences and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. ²⁶⁵Department of Cardiovascular Diseases, University of Siena, Siena, Italy. ²⁶⁶Otolaryngology Unit, University of Siena, Siena, Italy. ²⁶⁷Department of Internal Medicine, ASST Valtellina e Alto Lario, Sondrio, Italy. ²⁶⁸Study Coordinator Oncologia Medica e Ufficio Flussi, Sondrio, Italy. ²⁶⁹Department of Infectious and Tropical Diseases, University of Padova, Padua, Italy. ²⁷⁰First Aid Department, Luigi Curto Hospital, Polla, Salerno, Italy. ²⁷¹Local Health Unit-Pharmaceutical Department of Grosseto, Toscana Sud Est Local Health Unit, Grosseto, Italy. ²⁷²U.O.C. Laboratorio di Genetica Umana, IRCCS Istituto G. Gaslini, Genoa, Italy. ²⁷³Infectious Diseases Clinics, University of Modena and Reggio Emilia, Modena, Italy. ²⁷⁴Department of Respiratory Diseases, Azienda Ospedaliera di Cremona, Cremona, Italy. ²⁷⁵U.O.C. Medicina, ASST Nord Milano, Ospedale Bassini, Cinisello Balsamo, Italy. ²⁷⁶Istituto Auxologico Italiano, IRCCS, San Luca Hospital, Milan, Italy. ²⁷⁷Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy. ²⁷⁸University of Siena, DIISM-SAILAB, Siena, Italy. ²⁷⁹Department of Mathematics, University of Pavia, Pavia, Italy. ²⁸⁰University Cote d’Azur, Inria, CNRS, I3S, Maasai, Nice, France. ²⁸¹Independent Medical Scientist, Milan, Italy. ²⁸²Independent Data Scientist, Milan, Italy. ²⁸³Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, Milano, Italy. ²⁸⁴Scuola Normale Superiore, Pisa, Italy. ²⁸⁵CNR-Consiglio Nazionale delle Ricerche, Istituto di Biologia e Biotecnologia Agraria (IBBA), Milano, Italy. ³²⁴Present address: ERCEA (European Research Council Executive Agency), Bruxelles, Belgium.

The list of members and their affiliations can be found in the supplementary information.

BRACOVID Contributors

Alexandre C. Pereira²²², Jose E. Krieger²²², Emmanuelle Marques²²² & Cinthia E. Jannes²²²

The list of members and their affiliations can be found in the supplementary information.

[Paper] Translation of a Paper on COVID-19 and Genetics #1

Table of Contents

Genetic Mechanisms of Severe COVID-19

Results

GWAS Results

Replication

Mendelian Randomization

Transcriptome-Wide Association Study

Genetic Correlation

Discussion

Online Content

GenOMICC Consortium

GenOMICC Collaborators

Central management and laboratory team

Data analysis team

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

Good Hope Hospital, Birmingham, UK

Stepping Hill Hospital, Stockport, UK

Manchester Royal Infirmary, Manchester, UK

Royal Alexandra Hospital, Paisley, UK

Queen Elizabeth University Hospital, Glasgow, UK

Queen Alexandra Hospital, Portsmouth, UK

BHRUT (Barking Havering) - Queens Hospital and King George Hospital, Essex, UK

University College Hospital, London, UK

Royal Victoria Infirmary, Newcastle Upon Tyne, UK

Western Sussex Hospitals, West Sussex, UK

Salford Royal Hospital, Manchester, UK

The Royal Oldham Hospital, Manchester, UK

Pinderfields General Hospital, Wakefield, UK

Basildon Hospital, Basildon, UK

University Hospital of Wales, Cardiff, UK

Broomfield Hospital, Chelmsford, UK

Royal Brompton Hospital, London, UK

Nottingham University Hospital, Nottingham, UK

Royal Hallamshire Hospital and Northern General Hospital, Sheffield, UK

Royal Hampshire County Hospital, Hampshire, UK

Queens Hospital Burton, Burton-On-Trent, UK

New Cross Hospital, Wolverhampton, UK

Heartlands Hospital, Birmingham, UK

Walsall Manor Hospital, Walsall, UK

Stoke Mandeville Hospital, Buckinghamshire, UK

Sandwell General Hospital, Birmingham, UK

Royal Berkshire NHS Foundation Trust, Berkshire, UK

Charing Cross Hospital, St Mary’s Hospital and Hammersmith Hospital, London, UK

Dumfries and Galloway Royal Infirmary, Dumfries, UK

Bristol Royal Infirmary, Bristol, UK

Royal Sussex County Hospital, Brighton, UK

Whiston Hospital, Prescot, UK

Royal Glamorgan Hospital, Cardiff, UK

King’s Mill Hospital, Nottingham, UK

Fairfield General Hospital, Bury, UK

Western General Hospital, Edinburgh, UK

Northwick Park Hospital, London, UK

Royal Preston Hospital, Preston, UK

Royal Derby Hospital, Derby, UK

Sunderland Royal Hospital, Sunderland, UK

Royal Surrey County Hospital, Guildford, UK

Derriford Hospital, Plymouth, UK

Croydon University Hospital, Croydon, UK

Victoria Hospital, Kirkcaldy, UK