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[Paper] Translation of paper on novel coronaviruses and genetics #1

[Paper] Translation of paper on novel coronaviruses and genetics #1

Genetic mechanisms of severe disease in novel coronaviruses.

Date of receipt September 27, 2020
Acceptance date November 30, 2020
Accelerated article previews are available
Online publication date December 11, 2020
Cite this article as: Pairo-Castineira, E. et al.
Genetic mechanisms of severe disease
New coronaviruses. Nature https://doi.org/10.1038/

s41586-020-03065-y (2020).

Erola Pairo-Castineira1,2,325, Sara Clohisey1,325, Lucija Klaric2,325, Andrew D. Bretherick2,325, Konrad Rawlik1,325, Dorota Pasko3, Susan Walker3, Nick Parkinson1, Max Head Fourman1, Clark D. Russell1,4, 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 Hayward2,5, Jian Yang12,13, Julian Knight14, Charlotte Summers15, Manu Shankar-Hari16,17, Paul Klenerman14, Lance Turtle18, Antonia Ho19, Shona C. Moore18, Charles Hinds20, Peter Horby21, Alistair Nichol22,23,24, David Maslove25, Lowell Ling26, Danny McAuley27,28, Hugh Montgomery29, Timothy Walsh11, Alex Pereira30, Alessandra Renieri31,32, The GenOMICC Investigators*, The ISARIC4C Investigators*, The COVID-19 Human Genetics Initiative*, 23andMe Investigators*, BRACOVID Investigators*, Gen-COVID Investigators*, Xia Shen9,33,34, Chris P. Ponting2, Angie Fawkesv6, Albert Tenesa1,2,33, Mark Caulfield3,20, Richard Scott3,35, Kathy Rowan7, Lee Murphy6, Peter J. M. Openshaw36,37, Malcolm G. Semple18,38, Andrew Law1, Veronique Vitart2, James F. Wilson2,33 & J. Kenneth Baillie1,2,11 ✉

In serious diseases caused by Covid-19, there is host-mediated inflammation of the lungs and1、Increased mortality2。Host genetic variants associated with serious diseases may identify targets for therapeutic development mechanisms.3Here we report the results of the 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). The chr12q24.13 (rs10735079, p = 1.65 x 10) gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, and OAS3)-8)to identify and replicate novel, genome-wide significant associations. chr19p13.2 (rs2109069, p = 2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), chr19p13.3 (rs2109069, p = 3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9) ) and chr21q22.1 in the interferon receptor gene IFNAR2(rs2236757、p = 4.99××10-8)。Identify potential targets for diversion of approved drugs. Using Mendelian randomization, we found evidence supporting a causal link from low expression of IFNAR2 and high expression of TYK2 to life-threatening disease. Transcriptome-wide associations in lung tissue revealed that high expression of the monocyte/macrophage chemotaxis receptor CCR2 is associated with severe Covid-19. Our results identify a key host antiviral defense mechanism and a potent genetic signal associated with mediators of inflammatory organ damage in Covid-19. Both mechanisms may be suitable for targeted therapy with existing drugs. Large randomized clinical trials are essential before any changes can be made to clinical practice.

Because Covid-19 serious disease is caused in part by inflammatory damage affecting the lungs and pulmonary vessels1. There are at least two distinct biological components to the risk of mortality. Susceptibility to viral infection and the propensity to develop harmful lung inflammation.
life-threatening infection4and susceptibility to immunological diseases are both highly heritable.In particular, influenza6Respiratory viruses such as5Susceptibility to is known to be heritable and associated with specific genetic variants.7 Covid-19 、3p21.31of one locus has been repeatedly associated with hospitalization.
8,9As with other viral diseases10are several examples of loss-of-function mutants that affect essential immune processes that cause severe disease in young people. For example, TLR7,11and several related genes. in type 1 interferon signaling, including the receptor subunit IFNAR2.12Genome-wide studies have the potential to reveal completely new molecular mechanisms of serious disease in Covid-19.
This may provide a therapeutic target to modulate the host immune response and promote survival3
There is now strong evidence that serious illness caused by Covid-19 is qualitatively different from mild or moderate illness, even among hospitalized patients. Patterns of symptomatology differ13、There are several distinct disease phenotypes with markedly different responses to immunosuppressive therapy2。In patients without respiratory failure, treatment tends to cause harm. Corticosteroid use has tremendous benefits among patients with significant respiratory failure2。On this basis, we believe that patients with significant Covid-19 respiratory failure have a clear pathophysiology.
In the UK, the group of patients admitted to the emergency room is relatively homogeneous, with severe hypoxic respiratory failure being the typical presentation14。The active disease process in these patients responds markedly to corticosteroid therapy15Characterized by pulmonary inflammation such as diffuse alveolar damage, pulmonary macrophage/monocyte influx, mononuclear cell pulmonary arterial vasculitis, and microthrombus formation1,16。Host-directed therapy has long been a desire. Used to treat serious diseases caused by respiratory viruses17。 Identification of loci associated with susceptibility to Covid-19 may lead to diversion or specific targets for drug development3。 GenOMICC(Genetics Of Mortality In Critical Care、genomicc。org)has been recruiting patients with severe syndromes such as influenza, sepsis, and new infections for five years. To better understand the host mechanisms leading to life-threatening Covid-19, a genome-wide association study was conducted comparing patients with severe cases of Covid-19 with controls from the UK population genetics study.

Result

Critically ill cases were recruited through the GenOMICC study in 208 UK intensive care units, and hospitalized cases were recruited through the International Severe Acute Respiratory Infections Consortium (ISARIC) Coronavirus Clinical Characterization Consortium (4C) study.
DNA was extracted from high-quality whole blood and array-based genome-wide genotypes obtained from 2734 unique individuals (materials and methods).Genetic ancestry was inferred using principal component analysis and individuals from the 1000 Genomes Project as population references (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 of the subset of 1069 cases for which additional data are available are shown in Supplementary Figures 7-13 and Supplementary Table 2. The cases were critically representative of the British disease population.14 Substitution in this multi-ancestor cohort was performed using the TOPMed reference panel.
Ancestry-matched controls were selected from a large population-based cohort UK Biobank (one case from five controls). Controls with known positive Covid-19 tests were excluded. The inevitable presence of individuals in the control group who might exhibit a significant disease phenotype if exposed to SARS-CoV-2 would be expected to bias the association toward the null. The GWAS was performed separately for each ancestry group using PLINK logistic regression, accounting for age, sex, sufficient number of zip code deprivations, and principal components of ancestry. In addition to several standard filters (materials and methods) to minimize pseudocorrelations, whole genome sequences from a subset of 1613 cases were used to filter out variants that may have been badly called or attributed. Thus, 83937 of the 4469187 assigned variants passed the other quality control filters after the GWAS was removed.There was a high level of residual inflation in the South and East Asian ancestry groups, and results for these subgroups were not reliable (Extended Data Figure 1, Supplementary Figure 4 ). The largest ancestry group included 1676 individuals of European descent (EUR). This group was used in the primary analysis presented below.

GWAS Results

In the primary analysis (GenOMICC European cases versus UK Biobank controls), 15 independent association signals were genome-wide significant at p<5 × 10-8 after agglutination based on linkage disequilibrium (Supplementary Figure 1). Eight of these were successfully validated in GWAS using two independent population genetic studies (100,000 Genomes and Generation Scotland) as controls (Table 1) and thus proceeded to replication. Sex-specific GWAS of this group showed no sex-specific associations (Supplementary Table 1). Meta-analysis among different ethnic groups showed no additional associations (Supplementary Figure 3).

Duplication

Due to the lack of studies of sufficient size on Covid-19 critical illness, reproducibility was sought in a meta-analysis of data from 2415 hospitalized Covid-19 cases and 477741 controls from the Covid-19 Host Genetics Initiative (HGI, mixed lineage). This included a comparison of cases who reported being placed on a ventilator, receiving oxygen, or having pneumonia with controls who did not report a positive test. In addition to the previously reported locus on chr3 (rs73064425, OR=2.14, discovery p=4.77×10-30), we found robust replicates at four loci in GenOMICC for novel associations: locus on chr12 within the OAS gene cluster (rs 74956615, OR=1.59, discovery p=1.65 × 10-8), a locus near TY (rs74956615, OR=1.59, discovery p) 65 × 10-8), near TYK2 on chr19 (rs74956615, OR=1.4, discovery p = 2.3 × 10-8), DPP9 on chr19 (rs2109069, OR=1.36, discovery p = 3. 98 × 10-12), and on chromosome 21 locus including the IFNAR2 gene (rs2236757, OR=1.28, discovery p = 4.99×10-8) (Figure 1, Extended Data Table 2). To increase the power of the exploratory analysis, GenOMICC severe EUR (ncases = 1676, ncontrols = 8380), UGI hospitalized Covid-19 vs. the population without UK Biobank (B2, version 2) (ncases = 2415, ncontrols = 477741) and 23andMe broad respiratory phenotype (ncases = 1128, ncontrols = 679531), with an inverse variance meta-analysis performed between the two populations. This revealed one additional (non-replicated) locus of CCHCR1 to be genome-wide significant (a more stringent threshold of p<10-8 was used to account for the lack of replication opportunities for the meta-analysis) (Table 2).

Mendelian randomization

Mendelian randomization provides evidence of a causal relationship between exposure variables and outcomes.18 We used two-sample summary data Mendelian randomization to assess evidence supporting a causal effect of RNA expression (GTEx v7, whole blood) of various genes on the odds of significant Covid-19. We identified an a priori list of target genes associated with the mechanism of action of a number of host-targeted agents proposed to treat Covid-19 (Supplementary Table 3). Seven of these targets had appropriate loci of locally actionable expression quantitative trait loci (eQTL) in GTEx(v7). Of these, IFNAR2 remained significant after correction for multiple testing of 7 tests by the Bonferroni test (β -1.49, standard error 0.52, p = 0.0043; Supplementary Table 4). There is uncertain evidence of heterogeneity (HEIDII19 p = 0.015) and that the effect of this variant on Covid-19 severe disease may be mediated through other mechanisms, leading to underestimation or underestimation of the effect of IFNAR2 expression on the risk of severe disease indicate that IFNAR2 may be a potential therapeutic target. Next, transcriptome-wide Mendelian randomization was performed to quantify support for unselected genes as potential therapeutic targets. An instrument of 4,614 unique ensemble gene IDs was available. After correcting for multiple comparisons in this analysis, no genes were statistically significant (4,614 tests). After conservative filtering for heterogeneity (HEIDI p > 0.05), the minimum Mendelian randomization p for the mutant in chr19:10466123 = 0.00049 affected TYK2 expression. Nine other genes with nominally significant Mendelian randomization p-values (p<0.0051) were also brought forward 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). The Mendelian randomization signal with tent-directed effects was used to determine the IFNAR2(p = 7.5×10-4)and TYK2(p = 5.5×10-5;Supplementary Table 6)The results were significant at

Transcriptome-wide association studies

Transcriptome-wide association studies (TWAS) to correlate GWAS results with tissue-specific gene expression data by inferring gene expression from known gene variants associated with transcription product levels (eQTLs)21,22was performed. GTEx v8 data from two preselected disease-related tissues (whole blood and lung) were used for this analysis (Figure 2). A combined meta-TWAS analysis selected genes with p<0.05 in these tissues and incorporated eQTL data from other tissues in GTEX,23and optimized the power to detect differences in predicted expression in lung or blood. We found five genes with significant genome-wide differences in predicted expression (Supplementary Table 7). These included four genes with differential predicted expression in lung tissue (three genes on chr3. We also performed an informative meta-analysis (MAIC) of the results24and compared it to existing biological findings on host-virus interactions in Covid.H. H. K. Krause, M. A. Harris, and J. M. H. Harris, "Gene expression of the H. pylori gene," J. Biol. GenOMICC The TWAS results overlap more than any other data source with results from transcriptome, proteome, and CRISPR studies of host genes involved in Covid-19 (Extended Data Figure 2).

Genetic correlation

High Definition Likelihood (HDL) Method25Initial estimates of SNP-based heritability (proportion of phenotypic variance captured by additive effects at common SNPs) for severe Covid-19 using 0.065(SE = 0.019)Two additional analyses failed to detect a significant signal in two analyses: the first was an analysis using controls from the 100,000 Genomes Project (in which the matching to GenOMICC cases was not very close, which may limit the heritability estimates) and second, a small GWAS comparing some GenOMICC cases with UK Biobank controls, using BMI and age matching where possible. This second analysis was less powerful because many cases were not in close agreement(ncases = 1260;ncontrols = 6300;Supplementary Figure 14.). Future analyses would include rare variants in larger numbers of cases, which would provide a more comprehensive estimate of heritability. We also tested for genetic correlations with other traits, i.e., the extent to which underlying genetic components are shared with severe Covid-19; using HDL methods, we identified significant negative genetic correlations with educational achievement and intelligence. We also detected significant positive genetic correlations with a number of adiposity phenotypes, including body mass index and leg fat (Supplementary Figure 19). In addition, similar to GWAS results for other infectious and inflammatory diseases, there was a significant enrichment of variants with strong associations to promoters and enhancers (Supplementary Figure 18).

Discussion

We found and replicated a significant genetic association with the life-threatening Covid-19 (Figure 1).By focusing on critically ill patients, some of these associations are more likely to be related to late-stage immune-mediated disease associated with respiratory failure requiring invasive mechanical ventilation2.Importantly, the GWAS approach is unbiased and genome-wide, allowing for the discovery of entirely new pathophysiological mechanisms. Because genetic variation can be used to infer causality, the availability of genetic evidence supporting a therapeutic target greatly increases the probability of success in drug development. In particular, Mendelian randomization occupies a unique position in the hierarchy of clinical evidence.
Patients admitted to UK intensive care units in the first wave of Covid-19 were, on average, younger and had a lower comorbidity burden. The population studied here is defined by the propensity for severe respiratory failure due to Covid-19; GenOMICC recruited in 208 intensive care units (covering 95% of the ICU capacity in the UK) to ensure broad coverage of the genetic ancestry of UK patients (Extended Data Figure 3).
For external replication, the closest comparisons are the Covid-19 Host Genetics initiative's inpatient and population analyses and 23andMe's extensive respiratory phenotypes, which are generously shared with the international community. Similarly, complete summary statistics from GenOMICC are, genomicc.org/dataIt is published immediately in the
Despite differences in case definition, novel associations from the critical care study were robustly replicated in the combined data from the inpatient case study (Extended Data Table 2). The Mendelian randomization results suggesting a causal relationship between IFNAR2 and TYK2 were also statistically significant in the confirmatory analysis. Our findings reveal that Covid-19 severity is associated with at least two biological mechanisms: innate antiviral defenses (IFNAR2 and OAS genes), known to be important in the early stages of the disease, and a key mechanism in the late, life-threatening Covid-19 The two most important mechanisms are host-driven inflammatory lung injury (DPP9, TYK2 and CCR2), which is a life-threatening, host-driven inflammatory lung injury (DPP9, TYK2 and CCR2).
Interferons are host antiviral signaling mediators that stimulate the release of many essential components of the initial host response to viral infection30。Consistent with the beneficial role of type I interferons, increased expression of the interferon receptor subunit IFNAR2, Mendelian randomization finding p = 0.0043 (7 tests);Reproduction p = 7.5×10-4(1テスト)and reduced the odds of severe Covid-19. Within the assumptions of Mendelian randomization, this represents evidence for a protective role for IFNAR2 in Covid-19. rare loss-of-function mutations in IFNAR2 are associated with severe Covid-1912 and many other viral diseases31,32。This suggests that administration of interferon reduces the likelihood of severe Covid-19 disease, but our evidence does not allow us to distinguish the time of disease when such treatment may be effective. In addition, this early stage of disease, when viral load is high33suggests that this genetic effect may be mediated in
The variant rs10735079 (chr12, p = 1.65 × 10-8) is located in the interferon-inducible oligoadenylate synthase (OAS) gene cluster (OAS1, OAS2, OAS3; Figure 1). Our TWAS detected a significant association with predicted expression of OAS3 (Figure 2).OAS1 mutants are from Vietnam34 and China35The genes were implicated in susceptibility to SARS-CoV in candidate gene association studies conducted in These genes are mediators that activate the effector enzyme RNAse L(2',5'-Oligoadenylate 2-5A)It encodes an enzyme that produces This enzyme is also, Double-stranded RNA, a replication intermediate of coronaviruses36Disassemble the37。Betacoronavirus OC43 and MHV are host antiviral mediators 2-5A38makes a phosphodiesterase that cleaves the SARS-CoV-2, but SARS-CoV-2 is not known to have this ability. The OAS gene is also known to be involved in the production of endogenous phosphodiesterase 12 (PDE-12)activity degrades the host antiviral mediator 2-5A, making it a potential therapeutic target. In addition, PDE-12 inhibitors are available that potentiate such antiviral activity, and OAS-mediated39
19p13.3 (rs2109069, p = 3.98 × 1012)associated is an intronic variant of the gene encoding dipeptidyl peptidase 9 (DPP9). Variants at this locus are associated with idiopathic pulmonary fibrosis40 。associated is an intronic variant of the gene encoding dipeptidyl peptidase 9 (DPP9). Variants at this locus are associated with idiopathic pulmonary fibrosis41 、Antigen presentation, activation of inflammatory cells42 It has diverse intracellular functions such as43 。It is important to identify genes that may contribute to inflammatory organ damage; TYK2 is one of four genetic targets of JAK inhibitors such as baricitinib44 and was one of the nine candidate drugs we used to develop our a priori target list (Supplementary Table 3).The association between TYK2 expression and severe disease has also been confirmed in outside data sets.
3p21.31.8in the previous section, which replicates the findings of Ellinghaus et al. The very small p-value at this locus (p=4.77×10-30) may reflect the large size of our study and our focus on extreme severity.Many genes at this locus may explain the association. A systematic review and meta-analysis of experimental data on betacoronavirus infection provided biological support for the FYCO145。Our TWAS results show that variants in this region confer significant genome-wide differences in the predicted expression of CXCR6, CCR2, and CCR3 (Figure 2a).One, but not all, of these genes is likely to be an important mediator of serious disease.
The association of CCR2 (CC-chemokine receptor 2) expression, inferred from genotype, with severe disease is particularly strong in lung tissue (Figure 2b).CCR2 promotes monocyte/macrophage chemotaxis to inflammatory sites and increased expression of the canonical ligand for CCR2 (monocyte chemoattractant protein/MCP-1) in bronchoalveolar lavage fluid from the lungs of Covid-19 patients during mechanical ventilation46。Circulating MCP-1 levels are associated with more severe disease. Anti-CCR2 Monoclonal Antibody Therapy in the Treatment of Rheumatoid Arthritis Is Safe47。ABO locus previously associated with Covid-19,8 but not genome-wide significance in the GenOMICC Critical Illness Cohort48 。 Interestingly, the combined meta-analysis (Figure 1) shows a genome-wide near-significant signal at this locus, suggesting that this mutation may be associated with susceptibility to Covid-19, but not severe (Extended Data Figure 4).
Analysis of shared heritability revealed a positive correlation with adiposity. This does not imply causality, as a number of biases may be at play, but may reflect a combination of two effects. First, increased BMI and low socioeconomic status are strong risk factors for severe Covid-19,14 and second, UK biobank participants are disproportionately drawn from social groups that are underrepresented in obesity compared to the general population49
Because of the urgent need to complete and report this study, we drew controls from population genetic studies with systematic differences in population structure, demographics, and comorbidities that were genotyped using different techniques than the cases. Residual confounders are reflected in the genomic inflation (λ0.5) value of 1.099 in the primary analysis (Extended Data Figure 1). We genotyped the majority of subjects using two different methods (microarray and whole genome sequencing) and validated significant associations using two additional control groups (100,000 genomes and Generation Scotland), thereby reducing the false mitigated the risk of positive associations. 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 associations yielded an encouraging λ0.5 = 1.017 (Extended Data Figure 1).
Further studies are urgently needed to deepen these findings. Our MAIC results indicate that highly ranked genes in GenOMICC are likely to be involved in Covid in other studies (Extended Data Figure 2). We continue to recruit to the GenOMICC study in the hope that additional associations will exist and be detectable in a larger number of cases. Future studies using whole genome sequencing will explore the rarer end of the allele frequency spectrum for variants with increased susceptibility; in GenOMICC, cohorts are receiving invasive mechanical ventilation or are at high risk for requiring mechanical support The effect size is likely to be larger in patients determined by the treating physician to be strongly afflicted with an immediately life-threatening disease.
We have identified novel genetic associations between Covid-19 and severe disease. Some of these associations lead directly to the possibility of therapeutic approaches that enhance interferon signaling, antagonize monocyte activation and lung infiltration, or specifically target harmful inflammatory pathways. While this contributes significantly to the biological rationale supporting a particular therapy, each therapy must be validated in a large clinical trial before entering the clinic.

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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. The authors are also grateful to the authors for their contributions to this study. *A list of authors and their affiliations can be found 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. Miami plots show p-values for the GenOMICC GWAS in EUR (after validation, top panel) and meta-analysis including patients from Covid-19 Host Genetics Initiative and 23andMe (bottom panel); uncorrected p-values from GWAS analysis are shown. In the upper panel (GenOMICC), the red horizontal line indicates the genome-wide significance of the general variant at -log10(5×10 )-8, while in the lower panel (meta-analysis), the red horizontal line indicates the more stringent genome-wide significance threshold for the meta-analysis variant at -log10(10 )-8 This is indicated by the The quantile-quantile (QQ) plots are insets showing p-values for observed and expected values to indicate the genomic inflation rate (λ) for each analysis GenOMICC EUR λ= 1.099; GenOMICC-HGI-23m meta-analysis λ= 1.017. The full QQ plots are in Extended Data Figure 1 located at.

図2 TWAS結果の概要
Figure 2: Summary of TWAS results. a. Gene-level Manhattan plots showing raw p-value results from cross-tissue meta-TWAS analysis (see Methods). z-scores showing the direction of effect of genotype-estimated expression of transcripts encoding protein-coding genes in lung tissue (GTEX v8). Red highlights indicate genome-wide significance at p < 5 × 10-6.

Table 1 Read variants from independent significant regions across the genome

SNPchr:pos(b37)RiskAltRAFgccRAFukbORCIPgcc.ukbPgcc.gsPgcc.100kLocus
rs730644253:45901089TC0.150.072.11.88-2.454.8x10-302.9x10-273.6x10-32LZTFL1
rs93801426:29798794AG0.740.691.31.18-1.433.2x10-80.000911.8x10-8HLA-G
rs1433341436:31121426AG0.120.071.91.61-2.138.8x10-182.6x10-245.8x10-18CCHCR1
rs31312946:32180146GA0.90.861.51.28-1.662.8x10-81.3x10-102.3x10-8NOTCH4
rs1073507912:113380008AG0.680.631.31.18-1.421.6x10-82.8x10-94.7x10-6OAS1/3
rs210906919:4719443AG0.380.321.41.25-1.484x10-124.5x10-72.4x10-8DPP9
rs7495661519:10427721AT0.0790.051.61.35-1.872.3x10-82.2x10-133.9x10-6TYK2
rs223675721:34624917AG0.340.281.31.17-1.415x10-88.9x10-58.3x10-7IFNAR2

chr:pos-Chromosome and top SNP location (construct 37); Risk - allele; Alt - other allele; RAF - risk allele frequency; OR - effect size (odds ratio) for risk alleles in GenOMICC EUR analysis; CI-95% for odds ratio in GenOMICC EUR cohort Confidence Interval; P - p-value、Locus-The gene closest to the top SNP. subscript identifiersis the cohort used for the cases: gcc - GenOMICC EUR;and control group: ukb - British Biobank; gs - Generation Scotland; 100k - 10Indicates 10,000,000 genomes.

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

SNPchr:pos(b37)RiskAltORgccCIgccPgccORmetaCImetaPmetaLocus
rs713250883:45862952CT2.11.87-2.439.3x10-301.91.73-22.5x10-54LZTFL1
rs1433341436:31121426AG1.81.61-2.138.8x10-181.31.27-1.481.5x10-10CCHCR1
rs648986712:113363550TC1.31.15-1.376.9x10-71.21.14-1.259.7x10-10OAS1
rs210906919:4719443AG1.41.25-1.484x10-121.21.19-1.317x10-13DPP9
rs1108572719:10466123TC1.31.17-1.41.3x10-71.21.18-1.311.2x10-13TYK2
rs1305072821:34615210TC1.31.15-1.383x10-71.21.16-1.285.1x10-12IFNAR2

Because this is a meta-analysis of all available data, no external replication can be attempted, SNPs are included in this table if they meet the more stringent p-value threshold of p<10-8; SNP - strongest SNP at a 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 indicate a combined meta-analysis of all three studies (GenOMICC, HGI, 23andMe) for cases from the gcc - GenoMICC study, European ancestry, comparison with the UK Biobank and meta-European ancestry.

GenOMICCconsortium

GenOMICC Co-researcher

Sara Clohisey1, Peter Horby21, Johnny Millar1, Julian Knight14, Hugh Montgomery29, David Maslove25, Lowell Ling26, Alistair Nichol22, Charlotte Summers15, Tim Walsh11, Charles Hinds20, Malcolm G. Semple18,38, Peter J.M. Openshaw36,37, Manu Shankar-Hari16, Antonia Ho19, Danny McAuley27,28, Chris Ponting2, Kathy Rowan7 & J. Kenneth Baillie1,2,11

Central management and laboratory team

Fiona Griffiths1, Wilna Oosthuyzen1, Jen Meikle1, Paul Finernan1, James Furniss1, Ellie Mcmaster1, Andy Law1, Sara Clohisey1, J. Kenneth Baillie1,11, 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-Castineira1,2, Sara Clohisey1, Lucija Klaric2, Andrew D. Bretherick2, Konrad Rawlik1, Dorota Pasko3, Susan Walker3, Nick Parkinson1, Max Head Fourman1, Clark D Russell1,4, 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 Yang12,13, Xia Shen9,33,34, Chris P. Ponting2, Albert Tenesa1,2,33, Kathy Rowan7, Andrew Law1, Veronique Vitart2, James F. Wilson2,33, J. Kenneth Baillie1,2,11

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. Baillie1,2,11, 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.

A list of members and their affiliations can be found in the Supplementary Information.

ISARIC4C Consortium

ISARICC Co-researcher

J. Kenneth Baillie1,2,11, Malcolm G. Semple18,38, Peter J. M. Openshaw36,37, Gail Carson286, Beatrice Alex287, Benjamin Bach287, Wendy S. Barclay288, Debby Bogaert4, Meera Chand289, Graham S. Cooke290, Annemarie B. Docherty11,291, Jake Dunning36,292, Ana da Silva Filipe293, Tom Fletcher294, Christoper A. Green295, Ewen M. Harrison291, Julian A. Hiscox296, Antonia Ying Wai Ho293,297, Peter W. Horby21, Samreen Ijaz298, Saye Khoo299, Paul Klenerman300,301, Andrew Law1, 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 Sriskandan290,313, David Stuart314, Charlotte Summers15, Richard S. Tedder315,316,317, Emma C. Thomson293, AA Roger Thompson318, Ryan S. Thwaites36, Lance CW Turtle18,319 & 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 Analysis 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, OX3 7BN, 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.

A list of members and their affiliations can be found in the Supplementary Information.

HGI Consortium(Covid-19 Host Genetics Initiative)

Andrea Ganna218,219, Patrick Sulem220, David A. van Heel221, Mattia Cordioli218, Alessandra Renieri31,32, 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.

A list of members and their affiliations can be found in the Supplementary Information.

23andMe Contributor

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.

A list of members and their affiliations can be found in the Supplementary Information.

GEN-COVID Contributor

Francesca Mari31,32, Sergio Daga31, Margherita Baldassarri31, Elisa Benetti225, Simone Furini225, Chiara Fallerini31, Francesca Fava31,32, Floriana Valentino31, Gabriella Doddato31, Annarita Giliberti31, Rossella Tita32, Sara Amitrano32, Mirella Bruttini31,32, Susanna Croci31, Ilaria Meloni31, Anna Maria Pinto32, Elisa Frullanti31, Ilaria Meloni31, Caterina Lo Rizzo32, Francesca Montagnani226, Laura Di Sarno31, Andrea Tommasi31,32, 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 Rusconi244,245, 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 Capasso254,255,256, Roberta Russo254,255, Immacolata Andolfo254,255, Achille Iolascon254,255, Giuseppe Fiorentino257, Massimo Carella258, Marco Castori258, Giuseppe Merla258, Filippo Aucella259, Pamela Raggi260, Carmen Marciano260, Rita Perna260, Matteo Bassetti261,262, Antonio Di Biagio262, Maurizio Sanguinetti263,264, Luca Masucci263,264, 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 Crotti276,277, Nicola Picchiotti278,279, Marco Gori278,280, Chiara Gabbi281, Maurizio Sanarico282, Stefano Ceri283, Pietro Pinoli283, Francesco Raimondi284, Filippo Biscarini285,324 & Alessandra Stella285,323

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.

A list of members and their affiliations can be found in the Supplementary Information.

Bracovit Contributor

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

A list of members and their affiliations can be found in the Supplementary Information.