764 | Nature | Vol 617 | 25 May 2023 Article GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19 Erola Pairo-Castineira1,2,3,564, Konrad Rawlik1,564, Andrew D. Bretherick1,2,4, Ting Qi5,6, Yang Wu7, Isar Nassiri8, Glenn A. McConkey9, Marie Zechner1,3, Lucija Klaric2, Fiona Griffiths1,3, Wilna Oosthuyzen1,3, Athanasios Kousathanas10, Anne Richmond2, Jonathan Millar1,3,11, Clark D. Russell1, Tomas Malinauskas8, Ryan Thwaites12, Kirstie Morrice13, Sean Keating11, David Maslove14, Alistair Nichol15, Malcolm G. Semple16,17, Julian Knight8, Manu Shankar-Hari11,18, Charlotte Summers19, Charles Hinds20, Peter Horby21, Lowell Ling22, Danny McAuley23,24, Hugh Montgomery25, Peter J. M. Openshaw12,26, Colin Begg27, Timothy Walsh11, Albert Tenesa2,3,28, Carlos Flores29,30,31,32, José A. Riancho33,34,35, Augusto Rojas-Martinez36, Pablo Lapunzina37,38,39, GenOMICC Investigators*, SCOURGE Consortium*, ISARICC Investigators*, The 23andMe COVID-19 Team*, Jian Yang5,6, Chris P. Ponting2, James F. Wilson2,28, Veronique Vitart2, Malak Abedalthagafi40,41, Andre D. Luchessi42,43, Esteban J. Parra43, Raquel Cruz37,44, Angel Carracedo37,44,45,46, Angie Fawkes13, Lee Murphy13, Kathy Rowan47, Alexandre C. Pereira48, Andy Law3, Benjamin Fairfax8, Sara Clohisey Hendry1,3 & J. Kenneth Baillie1,2,3,11 ✉ Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). The design of the GenOMICC study and the rationale for focusing on critical illness has been previously described1,2. In brief, patients with confirmed COVID-19 requiring continuous cardiorespiratory monitor- ing or organ support (a generalizable definition for critical illness) were recruited in 2020–2022. We first performed ancestry-specific GWAS analyses according to the methods that we described previously1,2. Using the results of these GWAS analyses, previously reported results obtained using GenOMICC participants with whole-genome sequencing data2 and data from GenOMICC Brazil, we performed trans-ancestry and -platform meta-analyses within the GenOMICC study for a critically ill COVID-19 phenotype and a hospitalized COVID-19 phenotype (Extended Data Fig. 1). The results of these GenOMICC-only meta-analyses are presented for both critically ill and hospitalized phenotypes (Table 1 and Extended Data Fig. 2). To put these results into the context of existing knowledge, we performed comprehensive meta-analyses, drawing on further GWAS results, including data shared by the SCOURGE consor- tium and published data from the COVID-19 Human Genetics Initia- tive (HGIv6, 2021)4. The characteristics of the contributing studies are summarized in Supplementary Tables 13 and 14 for the critically ill and hospitalized phenotypes, with further details on each study provided in https://doi.org/10.1038/s41586-023-06034-3 Received: 22 November 2022 Accepted: 27 March 2023 Published online: 17 May 2023 Open access Check for updates A list of affiliations appears at the end of the paper. https://doi.org/10.1038/s41586-023-06034-3 http://crossmark.crossref.org/dialog/?doi=10.1038/s41586-023-06034-3&domain=pdf Nature | Vol 617 | 25 May 2023 | 765 Table 1 | Genome-wide significant associations with critical COVID-19, listing independent lead variants Chr:pos(b38) rsid EA OR ORCI P Pcond Nearest gene Citation 1:9067157 rs2478868 A 0.92 0.9–0.95 1.5 × 10−10 SLC2A5 GenOMICCnew 1:64948270 rs12046291 A 1.1 1.07–1.13 5.1 × 10−11 JAK1 GenOMICCnew 1:77501822 rs71658797 A 1.1 1.09–1.18 2.8 × 10−9 AK5 GenOMICCnew 1:155066988 rs114301457 T 2.4 1.81–3.18 1.5 × 10−9 EFNA4 GenOMICC2 1:155175305 rs7528026 A 1.3 1.25–1.44 1.5 × 10−15 TRIM46 GenOMICC2 1:155197995 rs41264915 A 1.2 1.17–1.26 7.6 × 10−24 THBS3 HGI18 1:155278322 rs11264349 A 0.94 0.92–0.97 7.3 × 10−5 3.9 × 10−13 HCN3 GenOMICCnew 2:60480453 rs1123573 A 1.1 1.09–1.15 1 × 10−14 BCL11A GenOMICC2 3:45796521 rs2271616 T 1.2 1.14–1.23 1.1 × 10−16 SLC6A20 HGI18 3:45818159 rs17713054* A 2 1.96–2.13 7.7 × 10−254 LZTFL1 SCGG19 3:45873093 rs35482426 CTT 0.53 0.5–0.57 6.1 × 10−91 LZTFL1 SCGG19 3:101790631 rs11706494 A 1.1 1.05–1.11 9.4 × 10−9 NXPE3 GenOMICCnew 3:146522652 rs343314 T 1.2 1.09–1.21 4.6 × 10−8 PLSCR1 GenOMICC2 4:25446871 rs7664615 A 1.1 1.07–1.14 1.5 × 10−8 ANAPC4 GenOMICCnew 4:105673359 rs72670002 A 1.1 1.09–1.21 4.4 × 10−8 ARHGEF38 GenOMICCnew 4:167824478 rs1073165 A 1.1 1.05–1.11 1.1 × 10−9 − GenOMICCnew 5:132422622 rs2269821 A 1.1 1.08–1.16 3 × 10−10 IRF1-AS1 GenOMICC2 6:31153455 rs111837807 T 0.8 0.77–0.84 8.6 × 10−26 CCHCR1 GenOMICC1 6:31571991 rs2071590 A 1.1 1.06–1.11 3.1 × 10−10 LTA GenOMICCnew 6:32702687 rs2858305 T 0.93 0.9–0.95 2.1 × 10−9 HLA-DQA1 GenOMICC2 6:41522644 rs41435745 C 1.4 1.31–1.51 1.5 × 10−20 FOXP4 HGI18 7:75623396 rs1179620 T 0.92 0.9–0.95 2.3 × 10−9 HIP1 GenOMICCnew 7:100032719 rs2897075 T 1.1 1.06–1.11 8.9 × 10−11 ZKSCAN1 GenOMICCnew 8:60532539 rs13276831 T 1.1 1.05–1.1 1.7 × 10−8 RAB2A GenOMICCnew 9:21206606 rs28368148 C 0.59 0.49–0.7 5.3 × 10−9 IFNA10 GenOMICC2 9:33425186 rs60840586 G 1.1 1.07–1.14 9.7 × 10−9 AQP3 SCOURGE20 9:133271182 rs879055593 T 1.1 1.1–1.16 1 × 10−16 ABO SCGG19 10:79946568 rs721917 A 0.93 0.9–0.95 7.6 × 10−9 SFTPD HGI4 11:1219991 rs35705950 T 0.86 0.82–0.89 3.8 × 10−14 MUC5B HGI4 11:34482745 rs61882275 A 0.88 0.86–0.91 1 × 10−22 ELF5 GenOMICC2 12:112919637 rs2660 A 1.1 1.08–1.13 2.8 × 10−15 OAS1 GenOMICC1 12:132481571 rs11614702 A 1.1 1.08–1.13 2.1 × 10−16 FBRSL1 GenOMICC2 13:112881427 rs12585036 T 1.2 1.12–1.18 9.6 × 10−22 ATP11A GenOMICC2 16:89196249 rs117169628 A 1.2 1.12–1.2 2.6 × 10−16 SLC22A31 GenOMICC2 17:40003082 rs12941811 T 0.93 0.91–0.95 1.1 × 10−9 PSMD3 GenOMICCnew 17:46085231 rs8080583 A 0.89 0.86–0.91 1.8 × 10−16 KANSL1 21 17:49863303 rs77534576 T 1.3 1.24–1.43 8.7 × 10−16 TAC4 21 19:4717660 rs12610495 A 0.8 0.77–0.82 9.1 × 10−51 DPP9 GenOMICC1 19:10352442 rs34536443 C 1.5 1.39–1.61 2.2 × 10−28 TYK2 GenOMICC1 19:10414696 rs142770866 A 1.2 1.19–1.3 9.4 × 10−21 PDE4A GenOMICCnew 19:48702915 rs516246 T 0.9 0.88–0.93 1.4 × 10−15 FUT2 GenOMICC2 19:50374423 rs35463555 A 1.1 1.07–1.13 1.9 × 10−13 NR1H2 HGI4 20:6489447 rs2326788 A 0.93 0.9–0.95 1.5 × 10−8 CASC20 GenOMICCnew 21:33229937 rs188401375 C 0.74 0.66–0.84 3.1 × 10−6 4.7 × 10−9 IFNAR2 GenOMICC1 21:33237639 rs9636867 A 0.83 0.81–0.85 5.2 × 10−48 IFNAR2 GenOMICC1 21:33287378 rs8178521 T 1.1 1.1–1.17 6.2 × 10−15 IL10RB GenOMICC2 21:33980963 rs76608815 T 1.2 1.14–1.23 7.4 × 10−17 ATP5PO GenOMICC2 21:41479527 rs915823 A 1.1 1.06–1.13 2.1 × 10−9 TMPRSS2 GenOMICCnew X:15523993 rs35697037 A 1 1.03–1.06 6.8 × 10−9 ACE2 HGI4 Chr:pos(b38), chromosome and position on human genome build 38; rsid, lead variant rsid; EA, effect allele; OR, odds ratio; ORCI, odds ratio confidence interval; P, P value against null hypothesis of odds ratio of one; Pcond, P value in conditional analysis in variants with P > 5 × 10−8; nearest gene, the nearest or most plausible nearby gene; citation, the first report of genome-wide significant association. ‘GenOMICCnew’ indicates findings presented in this Article. Additional details are provided in Supplementary Table 15 and full results of conditional analysis are provided in Supplementary Table 16. Supplementary Table 17 contains details of lead variants from the analysis of the hospitalized phenotype. 766 | Nature | Vol 617 | 25 May 2023 Article the Supplementary Information. We used a mathematical subtraction approach, as done in our previous work2, to remove signals of previous GenOMICC releases from HGIv6, yielding an independent dataset. As no replication cohorts exist for these meta-analyses, we used the heterogeneity across studies to assess the reliability of individual findings (Supplementary Table 15). Owing to the unusually extreme phenotype in the GenOMICC study, some heterogeneity is expected for the strongest associations when compared with studies with more permissive inclusion criteria. Importantly, significant heterogeneity was not detected for any of the findings that we report here (Supple- mentary Table 15). Comparing effect estimates between studies using a regression approach that takes into account estimation errors (Meth- ods), we detected systematic differences in effect sizes between studies (Extended Data Fig. 3). For example, effects for the HGI critical illness phenotype (which was designed to parallel the GenOMICC inclusion criteria) are smaller than those obtained using prospective recruitment in GenOMICC by a factor of 0.68. As the effect sizes in GenOMICC are consistently larger than other studies, and GenOMICC contributes a disproportionately large signal to meta-analyses of both critical and hospitalized phenotypes (Extended Data Fig. 4), between-study hetero- geneity is likely to reflect the careful case ascertainment and extreme phenotype in GenOMICC compared with other studies. We found 49 common genetic associations with critical COVID-19 meeting our criteria for genome-wide significance in the absence of heterogeneity (Extended Data Fig. 2 and Table 1). Findings from pre- vious reports were consistently replicated (Extended Data Table 2). Conditional analysis revealed two additional lead variants (Table 1) and statistical fine-mapping provided credible sets of putative causal variants for a majority of lead variants (Supplementary Figs. 27–44 and Supplementary Table 5). Gene-level analyses found 196 significantly associated genes at a Bonferroni-corrected threshold (Supplementary Table 10). There were no genome-wide significant differences in the effects between sexes in a sex-stratified meta-analysis using a subset of cohorts (Supplementary Fig. 1). Therapeutic implications Our analysis is limited to common variants that are detectable on geno- typing arrays and imputation panels. Although most lead variants are not directly causal, in some cases, they highlight molecular mecha- nisms that alter clinical outcomes in COVID-19, and may have direct therapeutic relevance. To investigate the disease mechanisms, we first quantified the effect of inferred gene expression on critical illness in three relevant tissue/cell types. Many of the genes that we have found to be implicated in critical COVID-19 (refs. 1,2) are highly expressed in the monocyte–macrophage system, which has poor coverage in existing expression quantitative trait loci (eQTL) datasets. For this reason, we constructed a new TWAS model in primary monocytes obtained from 176 individuals (Methods). We found significant associations after Bonferroni correction between critical COVID-19 and predicted gene expression in lung (33), blood (21), monocyte (37) and all-tissue (107) meta-analysis (Supplementary Table 2 and Supplementary Table 11). We extended these findings using generalized summary-level data Mendelian randomization (GSMR) for RNA expression (Fig. 2, Extended Data Table 1, Supplementary Figs. 11–18 and Supplementary Table 4). In parallel, we assessed the effect of genetically determined varia- tion in circulating protein levels on the critical illness phenotype using GSMR5. We identified 15 unique proteins linked to critical illness, as summarized in Extended Data Table 1 (Supplementary Table 3). Of the significant results, we found causal evidence implicating five new proteins in comparison to our previous GSMR analysis2: QSOX2, CREB3L4, myeloperoxidase (MPO), ADAMTS13 and mannose-binding lectin-2 (MBL2) (Supplementary Fig. 10). These include well-studied biomarkers and potential drug targets in sepsis—the innate immune pattern recognition receptor MBL2 and the neutrophil effector enzyme MPO. ADAMTS13 modulates von Willebrand-factor-mediated platelet thrombus formation and may have a role in the hypercoagulable state in critical COVID-19 (Extended Data Fig. 5). Three genes containing non-synonymous protein-coding changes associated with severe disease were also found to have significant effects from differential gene expression: SLC22A31 (ref. 2) (Fig. 1), SFTPD4 (Fig. 1) and TKY2 (ref. 1) (Extended Data Fig. 6). Further biological and clinical research will be required to dissect the genetic evidence at these loci. In the example of TYK2, there is now a therapeutic test of the genetic predictions. Our previous report of association between higher expression and critical illness1 led directly to the inclusion of a new drug, baricitinib, in a large clinical trial; the result demonstrated a clear therapeutic benefit3. This therapeutic signal is consistent across multiple trials, providing the first proof-of-concept for drug target identification using genetics in critical illness and infectious disease. To assess the immediate therapeutic use of our results for repur- posing of existing compounds, we considered the drug therapies under consideration by the UK COVID-19 Therapeutic Advisory Panel (UK-CTAP), a national independent review group supported by an expert due-diligence panel6. Consistent evidence from gene-level GWAS (Supplementary Table 6 and Supplementary Table 10) and post-GWAS analyses was identified for several licensed compounds (Supplementary Table 12). For example, we found an association in another gene encoding a protein that is inhibited by baricitinib and other JAK inhibitors—the intracellular signalling kinase, JAK1, which is stimulated by numerous cytokines including type I interferons and IL-6. Mendelian randomization analysis of RNA expression revealed a significant positive association between the expression of the gene encoding a canonical inflammatory cytokine, tumour necrosis factor (TNF), and severe disease (Fig. 2). This suggests that inhibition of TNF signalling may be an effective therapy in severe COVID-19. Our additional expression data in monocytes reveal a marked tissue-specific effect on expression of PDE4A. This phosphodiester- ase regulates the production of multiple inflammatory cytokines by myeloid cells. In contrast to the negative correlations seen in the lungs and blood, we show that a genetic tendency for higher expression of PDE4A in monocytes is associated with critical COVID-19 (Supplemen- tary Table 11). Inhibition of PDE4A by several existing drugs is under investigation in multiple inflammatory diseases7, reduces pulmonary endothelial permeability8 and appears to be safe in small clinical trials in patients with COVID-19. The postulated biological role of genes associated with critical COVID-19 in GWAS, TWAS and GSMR results is shown in Extended Data Fig. 5, which highlights the preponderance of genes with expression or functions in the mononuclear phagocyte system. This includes SLC2A5, encoding the GLUT5 fructose transporter, which is strongly inducible in primary macrophages in response to inflammatory stimulation9, and XCR1, a dendritic cell receptor with a critical role in cytotoxic T cell-mediated antiviral immunity10. NPNT, a significant meta-TWAS association in the genome-wide significant region on chromosome 4 (chr4:105673359; Supplementary Table 11), encodes a pulmonary basement membrane protein that may have a protective role in acute lung injury11. Host–pathogen interaction Our results also demonstrate the capacity of host genetics to reveal core mechanisms of disease. Multiple genes implicated in viral entry are associated with severe disease. In addition to ACE2, we detect a genome-wide significant association in TMPRSS2, a key host protease that facilitates viral entry that we have previously studied as a candi- date gene12. This effect may be viral-lineage specific13. A strong GWAS association is seen in RAB2A (Table 1), with TWAS evidence suggesting that more expression of this gene is associated with worse disease (Supplementary Table 11). RAB2A is highly ranked in our previous Nature | Vol 617 | 25 May 2023 | 767 meta-analysis by information content14 study of host genes implicated in SARS-CoV-2 interaction using in vitro and clinical data15, and is con- sistent with CRISPR screen data showing that RAB2A is required for viral replication16. Although our focus on critical illness enhances discovery power (Extended Data Fig. 4), it has the disadvantage of combining genetic signals for multiple stages in disease progression, including viral expo- sure, infection and replication, and development of inflammatory lung –1.0 –0.5 0 0.5 Exposure: eQTLGen b xy ICAM5.5124.62.3 ICAM5.8245.27.3 SELE ICAM1 PDGFRL ABO QSOX2 CD209 CREB3L4 FAM3D GOLM1 –0.2 –0.1 0 0.1 0.2 0.3 bxy E xp os ur e: p Q TL a b B C L1 1A P P A P D C 1B IC A M 5 IR F1 C E A C A M 3 A TG 16 L2 IF N A R 2 C C R 5 IS G 15 G A TA 2 X R C C 6 N S F P R R C 2A D A P 3 R P 11 -2 59 G 18 .2 D P P 9 C A 8 IF I6 B E N D 3P 3 IF I4 4L R P 11 -5 06 M 13 .3 IF I4 4 N TN 5 C X C R 6 A C 07 90 31 .1 S N R P D 2 IR F7 C C R 1 D D R 1 R P 11 -2 59 G 18 .3 R IT 1 A TP 6V 1G 2 C N P Y 4 O A S 1 R P 11 -2 59 G 18 .1 IF N A R 1 FA M 22 B LR R C 37 A 16 P R P 11 -1 19 F1 9. 2 C R H R 1- IT 1 FL T1 P 1 H LA -G LR R C 37 A 2 D N D 1P 1 R P 11 -7 07 O 23 .5 LI N C 00 64 9 H IP 1 H LA -S N A P S B K A N S L1 -A S 1 FC E R 1G O R M D L3 R P 11 -5 03 G 7. 2 M IC A G S D M B Z FP 57 S TA R D 10 H LA -U LR R C 37 A 4P C A T S LC 22 A 31 TT C 19 R P 11 -7 98 G 7. 5 S FT P D H C G 27 R P 11 -7 98 G 7. 6 TC F1 9 C C H C R 1 TN F C 7o rf 43 D E F8 C O R O 1B A B TB 2 M E D 24 A C S L6 H B B P 1 C D 79 B TY K 2 M U C 1 Fig. 2 | GSMR effect sizes. a,b, The predicted effect of change in protein concentration (a) and gene expression (b) on the risk of critical COVID-19 is shown for proteins and genes significantly linked to critical COVID-19 by GSMR (false-discovery rate (FDR) < 0.01). The bars show 95% confidence intervals. C O V ID -1 9 (b zy ) 0.05 0 –0.05 –0.10 –0.15 –0.8 –0.6 –0.4 –0.2 0 0.2 SLC22A31 (bzx) Extracellular space P474 Cytoplasm P474 Putative small-molecule transport pathway P130 P474 Q133 V134 L137 0.10 0.05 0 –0.05 –0.10 C O V ID 19 (b zy ) –0.3 –0.2 –0.1 0 0.1 0.2 0.3 SFTPD (bzx) M31 90° M31 A34 S33 P32 M31 T30 R29 H28 LD (r) with rs117169628 –0.20 0.17–0.22 0.88 0.01–0.10 LD (r) with rs721917 –0.30 0.03 0.05–0.08 0.19–0.21 0.50 Different chromosome 0.11 to –0.09 c a b d Membrane 90° Fig. 1 | Functional genomics analyses for SLC22A31 and SFTPD. a, Effect-size plot for the effect of multiple variants on SLC22A31 expression (eQTLgen, x axis) against increasing susceptibility to critical COVID-19 (βxy = 0.11; Pxy = 1.3 × 10−9). The colour shows linkage disequilibrium (LD) with the missense variant rs117169628. b, Three cartoon views of an AlphaFold22 model of putative solute carrier family 22 member 31 (SLC22A31; UniProtKB: A6NKX4). The side chains of Pro474 and interacting amino acids are shown as connected spheres. A putative channel for small-molecule transport across the cell membrane is indicated by a dashed circle. Pro474 is predicted to be located in the transmembrane helix and point towards a putative transport pathway of a small molecule. The risk variant, P474L (Ala at rs117169628) would be expected to introduce more flexibility to the transmembrane helix and might therefore affect the transport properties of SLC22A31. Pro474 is predicted to be in a tightly packed environment, and may therefore affect the folding of SLC22A31. c, Effect-size plot for effect of multiple variants on SFTPD expression (eQTLgen, x axis) against increasing susceptibility to critical COVID-19 (βxy = 0.16; Pxy = 9.7 × 10−6). Colour shows linkage disequilibrium with the missense variant rs721917. d, Three cartoon views of an AlphaFold22 model of pulmonary surfactant-associated protein D (SFTPD; UniProtKB: P35247). The side chain of the variant Met31 is shown as connected spheres. Met31 is predicted to be located in the secondary-structure-lacking region of SFTPD. In the diagram on the right, oxygen and nitrogen atoms are coloured red and blue respectively, and the sulfur atom is coloured yellow. https://alphafold.ebi.ac.uk/entry/A6NKX4 https://alphafold.ebi.ac.uk/entry/P35247 768 | Nature | Vol 617 | 25 May 2023 Article disease. From these data alone we cannot identify when in disease progression the causal effect is mediated, although clinical evidence helps to make some predictions17 (Extended Data Fig. 5). As most cases included were recruited before vaccinations and treatments became available (Extended Data Fig. 7), at present, our study does not have sufficient statistical power to dissect the genetic effects of treatments or vaccination. These effects may include the masking of true associa- tions, or the detection of genetic effects mediated by vaccine or drug response, rather than COVID-19 susceptibility. However, the absence of divergent genetic effects between studies (Supplementary Figs. 2–5) or consistent changes in effect allele frequency among cases over time (Supplementary Figs. 45–48) suggests that treatment and vaccination have not substantially affected the association between the specific variants that we report and the risk of critical illness. As we performed a meta-analysis of multiple studies that may have slightly different definitions of the phenotype, effect sizes dif- fer between studies (Supplementary Figs. 2–5). This, together with ancestry-specific effects1, may explain the heterogeneity in strong GWAS signals, such as the LZTFL1 signal in Table 1. Different studies also have sets of variants that are not completely overlapping, so P values between variants in high linkage disequilibrium are more different than expected. Although most of the studies contain individuals from multiple ancestries, a large majority of the individuals are of European ancestry. In future research, there is a scientific and moral imperative to include the full diversity of human populations. Together, these results deepen our understanding of the pathogenesis of critical COVID-19 and highlight new biological mechanisms of disease, several of which have immediate potential for therapeutic targeting. Online content Any methods, additional references, Nature Portfolio reporting summa- ries, source data, extended data, supplementary information, acknowl- edgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/s41586-023-06034-3. 1. Pairo-Castineira, E. et al. Genetic mechanisms of critical illness in COVID-19. Nature 591, 92–98 (2021). 2. Kousathanas, A. et al. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature 607, 97–103 (2022). 3. Abani, O. et al. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet 400, 359–368 (2022). 4. Pathak, G. A. et al. A first update on mapping the human genetic architecture of COVID-19. Nature 608, E1–E10 (2022). 5. Zhu, Z. et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat. Commun. 9, 224 (2018). 6. Chinnery, P. F. et al. Choosing drugs for UK COVID-19 treatment trials. Nat. Rev. Drug Discov. 21, 81–82 (2022). 7. Peng, T., Qi, B., He, J., Ke, H. & Shi, J. Advances in the development of phosphodiesterase-4 inhibitors. J. Med. Chem. 63, 10594–10617 (2020). 8. Sanz, M.-J. et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br. J. Pharmacol. 152, 481–92 (2007). 9. Forrest, A. R. R. et al. A promoter-level mammalian expression atlas. Nature 507, 462–470 (2014). 10. Brewitz, A. et al. CD8. Immunity 46, 205–219 (2017). 11. Wilson, C. L., Hung, C. F. & Schnapp, L. M. Endotoxin-induced acute lung injury in mice with postnatal deletion of nephronectin. PLoS ONE 17, e0268398 (2022). 12. David, A. et al. A common TMPRSS2 variant has a protective effect against severe COVID-19. Curr. Res. Transl. Med. 70, 103333 (2022). 13. Meng, B. et al. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. Nature https://doi.org/10.1038/s41586-022-04474-x (2022). 14. Li, B. et al. Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection. Nat. Commun. 11, 164 (2020). 15. Parkinson, N. et al. Dynamic data-driven meta-analysis for prioritisation of host genes implicated in COVID-19. Sci. Rep. 10, 22303 (2020). 16. Hoffmann, H.-H. et al. Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors. Preprint at bioRxiv https://doi.org/ 10.1101/2020.09.11.291716 (2020). 17. Russell, C. D., Lone, N. I. & Baillie, J. K. Comorbidities, multimorbidity and COVID-19. Nat. Med. 29, 334–343 (2023). 18. Niemi, M. E. K. et al. Mapping the human genetic architecture of COVID-19. Nature 600, 472–477 (2021). 19. Ellinghaus, D. et al. Genomewide association study of severe COVID-19 with respiratory failure. New Engl. J. Med. 383, 1522–1534 (2020). 20. Cruz, R. et al. Novel genes and sex differences in COVID-19 severity. Hum. Mol. Genet. 31, 3789–3806 (2022). 21. Degenhardt, F. et al. Detailed stratified GWAS analysis for severe COVID-19 in four European populations. Hum. Mol. Genet. 31, 3945–3966 (2022). 22. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2023, corrected publication 2023 1Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. 2MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. 3Roslin Institute, University of Edinburgh, Edinburgh, UK. 4Pain Service, NHS Tayside, Ninewells Hospital and Medical School, Dundee, UK. 5School of Life Sciences, Westlake University, Hangzhou, China. 6Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. 7Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. 8Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. 9Faculty of Biological Sciences, University of Leeds, Leeds, UK. 10Genomics England, London, UK. 11Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. 12National Heart and Lung Institute, Imperial College London, London, UK. 13Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK. 14Department of Critical Care Medicine, Queen’s University and Kingston Health Sciences Centre, Kingston, Ontario, Canada. 15Clinical Research Centre at St Vincent’s University Hospital, University College Dublin, Dublin, Ireland. 16NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences University of Liverpool, Liverpool, UK. 17Respiratory Medicine, Alder Hey Children’s Hospital, Institute in The Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK. 18Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. 19Department of Medicine, University of Cambridge, Cambridge, UK. 20William Harvey Research Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 21Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 22Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. 23Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK. 24Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, UK. 25UCL Centre for Human Health and Performance, London, UK. 26Imperial College Healthcare NHS Trust, London, UK. 27Royal Hospital for Children, Glasgow, UK. 28Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK. 29Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain. 30Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain. 31Centre for Biomedical Network Research on Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. 32Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. 33IDIVAL, Santander, Spain. 34Universidad de Cantabria, Santander, Spain. 35Hospital U M Valdecilla, Santander, Spain. 36Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud and Hospital San Jose TecSalud, Monterrey, Mexico. 37Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 38Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IDIPAZ, Madrid, Spain. 39ERN-ITHACA-European Reference Network, Paris, France. 40Genomic Research Department, King Fahad Medical City, Riyadh, Saudi Arabia. 41Department of Pathology & Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA. 42Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, Brazil. 43Department of Anthropology, University of Toronto at Mississauga, Mississauga, Ontario, Canada. 44Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. 45Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. 46Fundación Pública Galega de Medicina Xenómica, Sistema Galego de Saúde (SERGAS) Santiago de Compostela, Santiago de Compostela, Spain. 47Intensive Care National Audit & Research Centre, London, UK. 48Heart Institute, University of Sao Paulo, Butanta, Brazil. 564These authors contributed equally: Erola Pairo-Castineira, Konrad Rawlik. *A list of authors and their affiliations appears online. ✉e-mail: j.k.baillie@ed.ac.uk https://doi.org/10.1038/s41586-023-06034-3 https://doi.org/10.1038/s41586-022-04474-x https://doi.org/10.1101/2020.09.11.291716 https://doi.org/10.1101/2020.09.11.291716 http://creativecommons.org/licenses/by/4.0/ mailto:j.k.baillie@ed.ac.uk GenOMICC Investigators Co-Investigators J. Kenneth Baillie1,2,3,11, Colin Begg27, Sara Clohisey3, Charles Hinds20, Peter Horby21, Julian Knight8, Lowell Ling22, David Maslove14, Danny McAuley23,24, Johnny Millar3, Hugh Montgomery25, Alistair Nichol15, Peter J. M. Openshaw12,26, Alexandre C. Pereira48, Chris P. Ponting2, Kathy Rowan47, Malcolm G. Semple16,17, Manu Shankar-Hari18, Charlotte Summers19 & Timothy Walsh11 Management, Laboratory and Data Team Emma Aitkin3, Latha Aravindan49, Ruth Armstrong3, J. Kenneth Baillie3,11, Heather Biggs50, Ceilia Boz3, Adam Brown3, Primmy Chikowore3, Richard Clark13, Sara Clohisey3, Audrey Coutts13, Judy Coyle3, Louise Cullum3, Sukamal Das49, Nicky Day3, Lorna Donnelly13, Esther Duncan3, Angie Fawkes13, Paul Finernan3, Max Head Fourman3, Anita Furlong50, James Furniss3, Bernadette Gallagher3, Tammy Gilchrist13, Ailsa Golightly3, Fiona Griffiths3, Katarzyna Hafezi13, Debbie Hamilton3, Ross Hendry3, Naomi Kearns3, Andy Law3, Dawn Law3, Rachel Law3, Sarah Law3, Rebecca Lidstone-Scott3, Christen Lauder13, Louise Macgillivray13, Alan Maclean13, Hanning Mal3, Sarah McCafferty13, Ellie McMaster3, Jen Meikle3, Shona C. Moore16, Kirstie Morrice13, Lee Murphy13, Sheena Murphy49, Hellen Mybaya3, Miranda Odam3, Wilna Oosthuyzen3, Chenqing Zheng51, Jiantao Chen51, Nick Parkinson3, Trevor Paterson3, Petra Tucker50, Katherine Schon50, Andrew Stenhouse3, Mihaela Das49, Maaike Swets3,52, Helen Szoor-McElhinney3, Filip Taneski3, Lance Turtle16, Tony Wackett3, Mairi Ward3, Jane Weaver3, Nicola Wrobel13 & Marie Zechner3 Guys and St Thomas’ Hospital, London, UK Jacqueline Pan53, Neus Grau53, Tim Owen Jones53, Rosario Lim53, Martina Marotti53, Christopher Whitton53, Aneta Bociek53, Sara Campos53, Gill Arbane53, Manu Shankar-Hari53, Marlies Ostermann53, Mina Cha53, Fabiola DAmato53, Eirini Kosifidou53, Shelley Lorah53 & Kyma Morera53 James Cook University Hospital, Middlesbrough, UK Sarah Bircham54, Laura Brady54, Keith Hugill54, Jeremy Henning54, Stephen Bonner54, Evie Headlam54, Jessica Jones54, Abigail List54, Joanne Morley54, Amy Welford54, Bobette Kamangu54, Anitha Ratnakumar54 & Abiola Shoremekun54 Barts Health NHS Trust, London, UK Zoe Alldis55, Raine Astin-Chamberlain55, Fatima Bibi55, Jack Biddle55, Sarah Blow55, Matthew Bolton55, Catherine Borra55, Ruth Bowles55, Maudrian Burton55, Yasmin Choudhury55, Amber Cox55, Amy Easthope55, Patrizia Ebano55, Stavros Fotiadis55, Jana Gurasashvili55, Rosslyn Halls55, Pippa Hartridge55, Delordson Kallon55, Jamila Kassam55, Ivone Lancoma-Malcolm55, Maninderpal Matharu55, Peter May55, Oliver Mitchelmore55, Tabitha Newman55, Mital Patel55, Jane Pheby55, Irene Pinzuti55, Zoe Prime55, Oleksandra Prysyazhna55, Julian Shiel55, Melanie Taylor55, Carey Tierney55, Olivier Zongo55, Suzanne Wood55, Anne Zak55 & David Collier55 Royal Stoke University Hospital, Staffordshire, UK Manuela Mundy56, Christopher Thompson56, Lisa Pritchard56, Minnie Gellamucho56, David Cartlidge56, Nageswar Bandla56, Lucy Bailey56, Michelle Davies56, Jane Delaney56 & Leanne Scott56 North Middlesex University Hospital NHS trust, London, UK Marwa Abdelrazik57, Frater Alasdair57, David Carter57, Munzir Elhassan57, Arunkumar Ganesan57, Samuel Jenkins57, Zoe Lamond57, Dharam Purohit57, Kumar Rohit57, Malik Saleem57, Alanna Wall57, Kugan Xavier57, Dhanalaksmi Bakthavatsalam57, Kirolos Gehad57, Pakeerathan Gnanapragasam57, Kapil Jain57, Swati Jain57, Abdul Malik57, Naveen Pappachan57, Jeronimo Moreno-Cuesta57, Anne Haldeos57, Rachel Vincent57 & Maryjane Oziegb57 King’s College Hospital, London, UK Anna Cavazza58, Maeve Cockrell58, Eleanor Corcoran58, Maria Depante58, Clare Finney58, Ellen Jerome58, Abigail Knighton58, Monalisa Nayak58, Evita Pappa58, Rohit Saha58, Sian Saha58, Andrew Dodd58, Kevin O’Reilly58, Mark McPhail58, Emma Clarey58, Harriet Noble58 & John Smith58 Charing Cross Hospital, St Mary’s Hospital and Hammersmith Hospital, London, UK Phoebe Coghlan59, Stephen Brett59, Anthony Gordon59, Maie Templeton59, David Antcliffe59, Dorota Banach59, Sarah Darnell59, Ziortza Fernandez59, Eleanor Jepson59, Amal Mohammed59, Roceld Rojo59, Sonia Sousa Arias59, Anita Tamang Gurung59 & Jenny Wong59 The Royal Liverpool University Hospital, Liverpool, UK Jaime Fernandez-Roman60, David O. Hamilton60, Emily Johnson60, Brian Johnston60, Maria Lopez Martinez60, Suleman Mulla60, Alicia A. C. Waite60, Karen Williams60, Victoria Waugh60, Ingeborg Welters60, Jessica Emblem60, Maria Norris60 & David Shaw60 John Radcliffe Hospital, Oxford, UK Archana Bashyal61, Sally Beer61, Paula Hutton61, Stuart McKechnie61, Neil Davidson61, Soya Mathew61, Grace Readion61, Jung Ryu61 & Jean Wilson61 Addenbrooke’s Hospital, Cambridge, UK Shruti Agrawal62, Kay Elston62, Megan Jones62, Eoghan Meaney62, Petra Polgarova62, Muhammad Elbehery62, Charlotte Summers62, Esther Daubney62, Anthony Ng62, Jocelyn Marshall62, Nazima Pathan62, Katerina Stroud62 & Deborah White62 Nottingham University Hospital, Nottingham, UK Angela Andrew63, Saima Ashraf63, Amy Clark63, Martin Dent63, Margaret Langley63, Cecilia Peters63, Lucy Ryan63, Julia Sampson63, Shuying Wei63, Alice Baddeley63, Megan Meredith63, Lucy Morris63, Alexandra Gibbons63 & Lisa McLoughlin63 St George’s Hospital, London, UK Carlos Castro Delgado64, Victoria Clark64, Deborah Dawson64, Lijun Ding64, Georgia Durrant64, Obiageri Ezeobu64, Abiola Harrison64, William James Hurt64, Rebecca Kanu64, Ashley Kinch64, Susannah Leaver64, Ana Lisboa64, Jisha Mathew64, Kamal Patel64, Romina Pepermans Saluzzio64, John Rawlins64, Tinashe Samakomva64, Nirav Shah64, Christine Sicat64, Joana Texeira64, Joana Gomes De Queiroz64, Edna Fernandes Da Gloria64, Elena Maccacari64, Nikki Yun64, Soumendu Manna64, Sarah Farnell-Ward64, Maria Maizcordoba64, Maria Thanasi64 & Hawakin Haji Ali64 BHRUT (Barking Havering)—Queens Hospital and King George Hospital, Essex, UK Janice Hastings65, Lina Grauslyte65, Musarat Hussain65, Bobby Ruge65, Sam King65, Tatiana Pogreban65, Lace Rosaroso65, Helen Smith65, Mandeep-Kaur Phull65, Nikkita Adams65, George Franke65, Aparna George65, Erika Salciute65, Joanna Wong65, Karen Dunne65, Luke Flower65, Emma Sharland65 & Sukhmani Sra65 Royal Infirmary of Edinburgh, Edinburgh, UK Gillian Andrew66, Marie Callaghan66, Lucy Barclay66, Lucy Marshall66, Kenneth Baillie66, Maria Amamio66, Sophie Birch66, Kate Briton66, Sarah Clark66, Katerine Doverman66, Dave Hope66, Corrienne Mcculloch66, Scott Simpson66 & Jo Singleton66 Kingston Hospital, Surrey, UK Rita Fernandez67, Meryem Allen67, David Baptista67, Rebecca Crowe67, Jonathan Fox67, Jacyntha Khera67, Adam Loveridge67, India McKenley67, Eriko Morino67, Andres Naranjo67, Denise O’Connor67, Richard Simms67, Kathryn Sollesta67, Andrew Swain67, Harish Venkatesh67, Rosie Herdman-Grant67 & Anna Joseph67 Queen Alexandra Hospital, Portsmouth, UK Angela Nown68, Steve Rose68, David Pogson68, Helen Boxall68, Lutece Brimfield68, Helen Claridge68, Zoe Daly68, Shenu George68 & Andrew Gribbin68 Royal Gwent Hospital, Newport, UK Yusuf Cheema69, Sean Cutler69, Owen Richards69, Anna Roynon-Reed69, Shiney Cherian69, Anne Emma Heron69, Gemma Williams69, Tamas Szakmany69, Abby Waters69, Kim Collins69, Jill Dunhill69, Ffion Jones69, Rebecca Morris69, Lucy Ship69 & Amy Cardwell69 Royal Blackburn Teaching Hospital, Blackburn, UK Syamlan Ali70, Ravi Bhatterjee70, Rachel Bolton70, Srikanth Chukkambotla70, Dabheoc Coleman70, Jack Dalziel70, Joseph Dykes70, Christopher Fine70, Bethan Gay70, Wendy Goddard70, Drew Goodchild70, Rhiannan Harling70, Muhammad Hijazi70, Sarah Keith70, Meherunnisa Khan70, Roseanna Matt70, Janet Ryan-Smith70, Samuel Saad70, Philippa Springle70, Jacqueline Thomas70, Nick Truman70, Aayesha Kazi70, Matthew Smith70, Heather Collier70, Chloe Davison70, Stephen Duberley70, Jeanette Hargreaves70, Janice Hartley70, Tahera Patel70 & Ellen Smith70 Stepping Hill Hospital, Stockport, UK Alissa Kent71, Emma Goodwin71, Ahmed Zaki71, Clare Tibke71, Susan Hopkins71, Hywel Gerrard71, Matthew Jackson71, Sara Bennett71, Liane Marsh71 & Rebecca Mills71 Northumbria Healthcare NHS Foundation Trust, North Shields, UK Jessica Bell72, Helen Campbell72, Angela Dawson72, Steve Dodds72, Stacey Duffy72, Lisa Gallagher72, Gemma McCafferty72, Stacey Short72, Tracy Smith72, Kirsty Thomas72, Claire Walker72, Jessica Reynolds72, Bryan Yates72, Hayley McKie72, Maria Panteli72, Maria Thompson72 & Gail Waddell72 Countess of Chester Hospital, Chester, UK Sarah De Beger73, Azmerelda Abraheem73, Charlie Dunmore73, Rumanah Girach73, Rhianna Jones73, Emily London73, Imrun Nagra73, Farah Nasir73, Hannah Sainsbury73, Clare Smedley73, Stephen Brearey73, Caroline Burchett73, Kathryn Cawley73, Maria Faulkner73, Helen Jeffrey73, Peter Bamford73, Firdaus Shaikh73, Lauren Slack73 & Angela Davies73 Pinderfields General Hospital, Wakefield, UK Hollie Brooke74, Jose Cebrian Suarez74, Ruth Charlesworth74, Karen Hansson74, John Norris74, Alice Poole74, Rajdeep Sandhu74, Elizabeth Smithson74, Muthu Thirumaran74, Veronica Wagstaff74, Sarah Buckley74, Brendan Sloan74, Alastair Rose74, Amy Major74 & Alexandra Metcalfe74 Ninewells Hospital, Dundee, UK Christine Almaden-Boyle75, Pauline Austin75, Susan Chapman75, Alexandre Eros75, Louise Cabrelli75, Stephen Cole75, Clare Whyte75 & Matt Casey75 Croydon University Hospital, Croydon, UK Vasileios Bafitis76, George Tsinaslanidis76, Cassandra George76, Reena Khade76, Christopher Black76 & Sundar Raj Ashok76 Morriston Hospital, Swansea, UK Sean Farley77, Elaine Brinkworth77, Rachel Harford77, Carl Murphy77, Marie Williams77, Luke Newey77, Hannah Toghill77, Sophie Lewis77, Tabitha Rees77, Ceri Battle77, Mark Baker77, Jenny Travers77 & Karen Chesters77 Article Queen Elizabeth University Hospital, Glasgow, UK Nicola Baxter78, Andrew Arnott78, Gordan McCreath78, Christopher McParland78, Laura Rooney78, Malcolm Sim78, Steven Henderson78, Lynn Abel78, Carol Dalton78, Sophie Kennedy-Hay78, Lynn O’Donohoe78, Megan O’Hare78, Izabela Orlikowska78 & Natasha Parker78 Broomfield Hospital, Chelmsford, UK Fiona McNeela79, Amanda Lyle79, Alistair Hughes79, Jayachandran Radhakrishnan79 & Sian Gibson79 Heartlands Hospital, Birmingham, UK Hollie Bancroft80, Mary Bellamy80, Jacqueline Daglish80, Salma Kadiri80, Faye Moore80, Joanne Rhodes80, Mirriam Sangombe80, Zhane Peterkin80, James Scriven80 & Margaret Carmody80 Royal Sussex County Hospital, Brighton, UK Juliet Cottle81, Emily Peasgood81, Laura Ortiz-Ruiz de Gordoa81, Claire Phillips81 & Denise Skinner81 York Hospital, York, UK Zoe Cinquina82, Kate Howard82, Rosie Joy82, Samantha Roche82, Isobel Birkinshaw82, Joseph Carter82, Jo Ingham82, Nicola Marshall82, Harriet Pearson82 & Zoe Scott82 Queen Elizabeth Hospital, Birmingham, UK Jo Dasgin83, Jaspret Gill83, Annette Nilsson83, Amy Bamford83, Diana Hull83, James Scriven83, Nafeesah Ahmadhaider83, Michelle Bates83 & Christopher McGhee83 Royal Glamorgan Hospital, Pontyclun, UK Hannah Ellis84, Gwenllian Sera Howe84, Jayaprakash Singh84, Natalie Stroud84, Lisa Roche84, Ceri Lynch84, Bethan Deacon84, Carla Pothecary84, Justyna Smeaton84 & Kevin Agravante84 Barnet Hospital, London, UK Vinodh Krishnamurthy85, Cynthia Diaba85, Lincy John85, Lai Lim85 & Rajeev Jha85 Wythenshawe Hospital, Manchester, UK Jasmine Egan86, Timothy Felton86, Susannah Glasgow86, Grace Padden86, Ozerah Choudhr86, Joanne Bradley-Potts86, Stuart Moss86, Saejohn Lingeswaran86, Peter Alexander86, Craig Brandwood86, Sofia Fiouni86, Luke Ward86, Schvearn Allen86, Jane Shaw86 & Christopher Smith86 Medway Maritime Hospital, Gillingham, UK Oluronke Adanini87, Rebecca Collins87, Maines Msiska87, Linda Ofori87, Nikhil Bhatia87 & Hayley Dolan87 Royal Berkshire NHS Foundation Trust, Berkshire, UK Mark Brunton88, Jess Caterson88, Holly Coles88, Liza Keating88, Emma Tilney88, Nicola Jacques88, Matthew Frise88, Jennifer Armistead88, Shauna Bartley88, Parminder Bhuie88, Sabi Rai88 & Gabriela Tomkova88 Whiston Hospital, Prescot, UK Sandra Greer89, Karen Shuker89 & Ascanio Tridente89 The Royal Oldham Hospital, Manchester, UK Emma Dobson90, Jodie Hunt90, Redmond Tully90, Joy Dearden90, Andrew Drummond90, Prakash Kamath90, Emily Bullock90, Michelle Mulcahy90, Shelia Munt90, Grainne O’Connor90, Jennifer Philbin90, Chloe Rishton90, Chloe Scott90 & Sarah Winnard90 Chesterfield Royal Hospital Foundation Trust, Chesterfield, UK Nurkamalia Hasni91, Rachel Gascoyne91, Joanne Hawes91, Kelly Pritchard91, Lesley Stevenson91, Amanda Whileman91, Sarah Beavis91, Lauren Bishop91, Cindy Cart91, Katie Dale91, Mary Kelly-Baxter91, Adam Mendelski91, Emma Moakes91, Rheanna Smith91, Jan Woodward91 & Stephanie Wright91 Aberdeen Royal Infirmary, Aberdeen, UK Angela Allan92, Adriana Botello92, Jade Liew92, Jasmine Medhora92, Erin Trumper92, Felicity Savage92, Teresa Scott92, Marc Place92 & Callum Kaye92 Royal Devon and Exeter Hospital, Exeter, UK Sarah Benyon93, Suzie Marriott93, Linda Park93, Helen Quinn93, Daisy Skyes93, Lily Zitter93, Kizzy Baines93, Elizabeth Gordon93, Samantha Keenan93 & Andrew Pitt93 Glasgow Royal Infirmary, Glasgow, UK Katharine Duffy94, Jane Ireland94, Gary Semple94, Lynne Turner94, Susanne Cathcart94, Dominic Rimmer94, Alex Puxty94, Kathryn Puxty94, Andrew Hurst94, Jennifer Miller94, Susan Speirs94 & Lauren Walker94 Blackpool Victoria Hospital, Blackpool, UK Zena Bradshaw95, Joanna Brown95, Sarah Melling95, Stephen Preston95, Nicola Slawson95, Scott Warden95, Alanna Beasley95, Emma Stoddard95, Leonie Benham95, Jason Cupitt95, Melanie Caswell95, Lisa Elawamy95 & Ashleigh Wignall95 Southampton General Hospital, Southampton, UK Belinda Roberts96, Hannah Golding96, Samantha Leggett96, Michelle Male96, Martyna Marani96, Kirsty Prager96, Toran Williams96, Kim Golder96, Oliver Jones96, Rebecca Cusack96, Clare Bolger96, Rachel Burnish96, Michael Carter96, Susan Jackson96, Karen Salmon96 & Jonathan Biss96 Ashford and St Peter’s Hospital, Surrey, UK Maia Aquino97, Maria Croft97, Victoria Frost97, Ian White97 & Keshnie Govender97 Derriford Hospital, Plymouth, UK Natasha Webb98, Liana Stapleton98, Colin Wells98, Nikitas Nikitas98, Ana Sanchez-Rodriguez98, Kayleigh Spencer98 & Bethan Stowe98 East Surrey Hospital, Redhill, UK Yvonne Izzard99, Michelle Poole99, Sonja Monnery99, Sallyanne Trotman99, Valerie Beech99, Edward Combes99 & Teishel Joefield99 Poole Hospital, Poole, UK Patrick Covernton100, Sarah Savage100, Elizabeth Woodward100, Julie Camsooksai100, Henrik Reschreiter100, Charlotte Barclay100, Yasmin DeAth100, Judith Dube100, Charlotte Humphrey100, Sarah Jenkins100, Emma Langridge100, Rebecca Milne100, Beverley Wadams100 & Megan Woolcock100 Royal Alexandra Hospital, Paisley, UK Michael Brett101, Brian Digby101, Lisa Gemmell101, James Hornsby101, Patrick MacGoey101, Pauline O’Neil101, Richard Price101, Radha Sundaram101, Lynn Abel101, Natalie Rodden101, Nicola Thomson101, Kevin Rooney101, Susan Currie101, Natasha Parker101, Lauren Walker101 & Philip Henderson101 St James’s University Hospital and Leeds General Infirmary, Leeds, UK Bethan Ogg102, Simon Whiteley102, Liz Wilby102, Kate Long102, Shailamma Matthew102, Sheila Salada102, Susan Trott102, Sarah Watts102, Zoe Friar102 & Abigail Speight102 Bedford Hospital, Bedford, UK Victoria Bastion103, Humza Chandna103, Brice Djeugam103, Muhammad Haseeb103, Harriet Kent103, Gamu Lubimbi103, Sophie Murdoch103, Alastair Thomas103, Beena David103, Rachel Lorusso103, Ana Vochin103, Melchizedek Penacerrada103 & Retno Wulandari103 Southport and Formby District General Hospital, Ormskirk, UK Charlotte Heath104, Srinivas Jakkula104, Anna Morris104, Ashar Ahmed104, Arvind Nune104, Claire Buttriss104 & Emma Whitaker104 The Tunbridge Wells Hospital and Maidstone Hospital, Kent, UK Miriam Davey105, David Golden105, Amy Acklery105, Fabio Fernandes105, Bec Seaman105 & Victoria Earl105 Queen Elizabeth Hospital, Woolwich, London, UK Amy Collins106, Waqas Khaliq106, Rachel Adam106 & Estefania Treus106 North Manchester General Hospital, Manchester, UK Sarah Holland107, Jordan Alfonso107, Bethan Blackledge107, Michelle Bruce107, Laura Jayne Durrans107, Ayaa Eltayeb107, Jade Harris107, Samuel Hey107, Martin Hruska107, Thomas Lamb107, Joanne Rothwell107, Adele Fitzgerald107, Gabriella Lindergard107, Helen T-Michael107, Tracey Duncan107, Sharon Baxter-Dore107, Lisa Cooper107, Claire Fox107, Jacinta Guerin107, Tracey Hodgkiss107 & Karen Connolly107 Royal Victoria Infirmary, Newcastle Upon Tyne, UK Paul McAlinden108, Victoria Bridgett108, Maggie Fearby108, A. Gulati108, Helen Hanson108, Sinead Kelly108, Louise McCormack108, Rachel Nixon108, Philip Robinson108, Victoria Slater108, Elaine Stephenson108, Andrea Webster108, K. Webster108, Carole Hays108, Anne Hudson108, Bijal Patel108, Ian Clement108, John Davis108, Sarah Francis108 & Douglas Jerry108 Hull Royal Infirmary, Hull, UK Caroline Abernathy109, Louise Foster109, Andrew Gratrix109, Llucia Cabral-Ortega109, Matthew Hines109, Victoria Martinson109, Elizabeth Stones109 & Karen Winter109 Manchester Royal Infirmary, Manchester, UK Esther Barrow110, Katharine Wylie110, Deborah Baines110, Katie Birchall110, Laurel Kolakaluri110, Richard Clark110, Anila Sukumaran110, Craig Brandwood110, Melanie Barker110, Deborah Paripoorani110, Lara Smith110 & Charlotte Taylor110 Royal Derby Hospital, Derby, UK Charlotte Downes111, Melanie Hayman111, Katie Riches111, Priya Daniel111, Deepak Subramanian111, Kathleen Holding111, Mary Hilton111, Carly McDonald111 & Georgina Richardson111 Aintree University Hospital, Liverpool, UK Georgia Halladay112, Peter Harding112, Amie Reddy112, Ian Turner-Bone112, Laura Wilding112, Robert Parker112, Michaela Lloyd112, Leanne Smith112 & Charlie Kelly112 Fairfield General Hospital, Bury, UK Maria Lazo113, Alan Neal113, Olivia Walton113, Julie Melville113, Jay Naisbitt113, Emily Bullock113 & Rosane Joseph113 Norfolk and Norwich University hospital (NNUH), Norwich, UK Sara Callam114, Lisa Hudig114, Jocelyn Keshet-Price114, Katie Stammers114, Karen Convery114, Georgina Randell114 & Deirdre Fottrell-Gould114 Milton Keynes University Hospital, Milton Keynes, UK Esther Mwaura115, Sara-Beth Sutherland115, Richard Stewart115, Louise Mew115 & Lynn Wren115 Good Hope Hospital, Birmingham, UK Laura Thrasyvoulou116, Heather Willis116, James Scriven116, Bridget Hopkins116, Daniel Lenton116 & Abigail Roberts116 Queen Elizabeth Hospital Gateshead, Gateshead, UK Maria Bokhari117, Rachael Lucas117, Wendy McCormick117, Jenny Ritzema117, Vanessa Linnett117, Amanda Sanderson117 & Helen Wild117 Royal Bolton Hospital, Bolton, UK Rebecca Flanagan118, Robert Hull118, Kat Rhead118, Emma McKenna118, Gareth Hughes118, Jennifer Anderson118, Kelly Jones118, Scott Latham118 & Heather Riley118 Tameside General Hospital, Ashton Under Lyne, UK Martina Coulding119, Martyn Clark119, Jacqueline McCormick119, Oliver Mercer119, Darsh Potla119, Hafiz Rehman119, Heather Savill119, Victoria Turner119, Edward Jude119 & Susan Kilroy119 Salford Royal Hospital, Manchester, UK Elena Apetri120, Cathrine Basikolo120, Bethan Blackledge120, Laura Catlow120, Matthew Collis120, Reece Doonan120, Jade Harris120, Alice Harvey120, Karen Knowles120, Stephanie Lee120, Diane Lomas120, Chloe Lyons120, Liam McMorrow120, Angiy Michael120, Jessica Pendlebury120, Jane Perez120, Maria Poulaka120, Nicola Proudfoot120, Kathryn Slevin120, Vicky Thomas120, Danielle Walker120, Paul Dark120, Bethan Charles120, Danielle McLaughlan120, Melanie Slaughter120, Dan Horner120, Kathryn Cawley120 & Tracy Marsden120 Great Ormond St Hospital and UCL Great Ormond St Institute of Child Health NIHR Biomedical Research Centre, London, UK Joyann Andrews121, Emily Beech121, Olugbenga Akinkugbe121, Alasdair Bamford121, Holly Belfield121, Gareth A. L. Jones121, Tara McHugh121, Hamza Meghari121, Samiran Ray121, Ana Luisa Tomas121, Lauran O’Neill121, Mark Peters121, Michael Bell121, Sarah Benkenstein121, Catherine Chisholm121, Charlene Davies121, Klaudia Kupiec121 & Caroline Payne121 Southmead Hospital, Bristol, UK Joanna Halls122, Hayley Blakemore122, Elizabeth Goff122, Kati Hayes122, Kerry Smith122, Deanna Stephens122, Ruth Worner122, Borislava Borislavova122, Beverley Faulkner122, Matt Thomas122, Ruth Cookson122, Emma Gendall122, Georgina Larman122, Rebecca Pope122 & Artur Smalira122 William Harvey Hospital, Ashford, UK Victoria Priestley123, Tracey Cosier123, Gemma Millen123, James Rand123, Natasha Schumacher123, Roxana Sandhar123, Heather Weston123, Neil Richardson123 & Lucy Cooper123 Arrowe Park Hospital, Wirral, UK Cathy Jones124, Ya-Wen Jessica Huang124, Reni Jacob124, Craig Denmade124 & Lewis McIntyre124 Royal Hampshire County Hospital, Hampshire, UK Dawn Trodd125, Jane Martin125, Geoff Watson125, Emily Bevan125 & Caroline Wreybrown125 Bradford Royal Infirmary, Bradford, UK Shereen Bano126, Ruth Bellwood126, Michael Bentley126, Matt Bromley126, Lucy Gurr126, Camilla Ledgard126, Janet McGowan126, Kate Pye126, Kirsten Sellick126, Amelia Stacey126, Deborah Warren126, Brian Wilkinson126, Louise Akeroyd126, Huma Shafique126, James Morgan126, Susan Shorter126, Rachel Swinger126, Emily Waters126 & Tom Lawton126 Glan Clwyd Hospital, Bodelwyddan, UK Elizabeth Allan127, Kate Darlington127, Ffyon Davies127, Llinos Davies127, Jack Easton127, Sumit Kumar127, Richard Lean127, Callum Mackay127, Richard Pugh127, Xinyi Qiu127, Stephanie Rees127, Jeremy Scanlon127, Joanne Lewis127, Daniel Menzies127, Annette Bolger127, Gwyneth Davies127, Jennifer Davies127, Esther Garrod127, Helen Jones127, Rachel Manley127 & Hannah Williams127 Royal Bournemouth Hospital, Bournemouth, UK Jordan Frankham128, Sally Pitts128, Nigel White128, Debbie Branney128 & Heather Tiller128 Bristol Royal Infirmary, Bristol, UK Georgia Efford129, Zoe Garland129, Lisa Grimmer129, Bethany Gumbrill129, Rebekah Johnson129, Katie Sweet129, Jeremy Bewley129, Christina Coleman129, Katie Corcoran129, Eva Maria Hernandez Morano129, Rachel Shiel129, Denise Webster129, Josephine Bonnici129, Eleanor Daniel129 & Abbie Dell129 University Hospital North Durham, Darlington, UK and Darlington Memorial Hospital, Darlington, UK Melanie Kent130,131, Ami Wilkinson130,131, Ellen Brown130,131, Andrea Kay130,131, Suzanne Campbell130,131, Amanda Cowton130,131, Mark Birt130,131, Vicki Greenaway130,131, Kathryn Potts130,131, Clare Hutton130,131 & Andrew Shepperson130,131 Basildon Hospital, Basildon, UK Miranda Forsey132, Alice Nicholson132, Mark Vertue132, Joanne Riches132, Agilan Kaliappan132 & Anne Nicholson132 University College Hospital, London, UK Niall MacCallum133, Eamon Raith133, Georgia Bercades133, Ingrid Hass133, David Brealey133, Gladys Martir133, Anna Reyes133, Deborah Smyth133 & Maria Zapatamartinez133 Whittington Hospital, London, UK Ana Alvaro134, Champa Jetha134, Louise Ma134, Lauren Booker134, Loreta Mostoles134, Anezka Pratley134, Abdelhakim Altabaibeh134, Chetan Parmar134 & Kayleigh Gilbert134 Western General Hospital, Edinburgh, UK Susie Ferguson135, Amy Shepherd135, Sheila Morris135, Jo Singleton135, Rosie Baruah135, Maria Amamio135, Sophie Birch135, Kate Briton135, Sarah Clark135, Katherine Doverman135, Lucy Marshall135 & Scott Simpson135 Ipswich Hospital, Ipswich, UK Georgina Lloyd136, Stephanie Bell136, Vanessa Rivers136 & Bally Purewal136 Hereford County Hospital, Hereford, UK Kate Hammerton137, Susan Anderson137, Janine Birch137, Emma Collins137 & Ryan Oleary137 Sunderland Royal Hospital, Sunderland, UK Sarah Cornell138, Jordan Jarmain138, Kimberley Rogerson138, Fiona Wakinshaw138, Lindsey Woods138, Anthony Rostron138, Zeynep Elcioglu138 & Alistair Roy138 Queens Hospital Burton, Burton-On-Trent, UK Gillian Bell139, Holly Dickson139, Louise Wilcox139, Amro Katary139 & Katy English139 Musgrove Park Hospital, Taunton, UK Joanne Hutter140, Corinne Pawley140, Patricia Doble140, Charmaine Shovelton140, Marius Vaida140, Rebecca Purnell140 & Ashly Thomas140 The Royal Papworth Hospital, Cambridge, UK Lenka Cagova141, Adama Fofano141, Helen Holcombe141, Alice Michael Mitchell141, Lucy Mwaura141, Krithivasan P. Raman141, Lucie Garnr141, Sue Mepham141, Kitty Paques141, Alain Vuylsteke141, Jennifer Mackie141, Carmen Pearn141 & Julie Zamikula141 University Hospital Lewisham, London, UK Mark Birt142, Estefania Treus Gude142, Maggie Nyirenda142, Lisa Capozzi142, Rosie Reece-Anthony142, Waqas Khaliq142, Hazma Noor142 & Alfa Cresia Nilo142 The Princess Alexandra Hospital, Harlow, UK Michelle Grove143, Amelia Daniel143, Amy Easthope143, Joanne Finn143, Nikki White143, Rajnish Saha143, Bibi Badal143 & Karen Ixer143 University Hospital of Wales, Cardiff, UK Donna Duffin144, Ben Player144, Helen Hill144, Jade Cole144, Jenny Brooks144, Michelle Davies144, Rhys Davies144, Lauren Hunt144, Emma Thomas144 & Angharad Williams144 West Middlesex Hospital, Isleworth, UK Metod Oblak145, Mini Thankachen145, Jamie Irisari145, Amrinder Sayan145 & Monica Popescu145 Royal Albert Edward Infirmary, Wigan, UK Cheryl Finch146, Andrew Jamieson146, Alison Quinn146, Joshua Cooper146, Sarah Liderth146 & Natalia Waddington146 Stoke Mandeville Hospital, Buckinghamshire, UK Iona Burn147, Katarina Manso147, Ruth Penn147, Julie Tebbutt147, Danielle Thornton147, James Winchester147, Geraldine Hambrook147 & Pradeep Shanmugasundaram147 Royal Lancaster Infirmary, Lancaster, UK Jayne Craig148, Kerry Simpson148, Andrew Higham148 & Louise Sibbett148 Basingstoke and North Hampshire Hospital, Basingstoke, UK Sheila Paine149, Annabel Reed149, Jo-Anna Conyngham149, McDonald Mupudzi149, Rachel Thomas149, Mary Wright149, Denise Griffin149, Richard Partridge149, Maria Alvarez Corral149, Nycola Muchenje149, Mildred Sitonik149 & Caroline Wrey Brown149 Worthing Hospital, Worthing, UK and St Richard’s Hospital, Chichester, UK Aaron Butler150,151, Linda Folkes150,151, Heather Fox150,151, Amy Gardner150,151, David Helm150,151, Gillian Hobden150,151, Kirsten King150,151, Jordi Margalef150,151, Michael Margarson150,151, Tim Martindale150,151, Emma Meadows150,151, Dana Raynard150,151, Yvette Thirlwall150,151, Yolanda Baird150,151, Raquel Gomez150,151, Darren Martin150,151, Luke Hodgson150,151, Clinton Corin150,151, Erikka Sidall150,151, Densie Szabo150,151 & Sharon Floyd150,151 Article The Alexandra Hospital, Redditch and Worcester Royal Hospital, Worcester, UK Hannah Davies152, Karen Austin152, Olivia Kelsall152, Hannah Wood152, Hannah Davies152, Peter Anderson152, Katie Archer152, Andrew Burtenshaw152, Sarah Clayton152, Naiara Cother152, Nicholas Cowley152, Caroline Davis152, Stephen Digby152, Alison Durie152, Alison Harrison152, Emma Low152, Michael McAlindon152, Alex McCurdy152, Aled Morgan152, Tobias Rankin152, Jessica Thrush152, Helen Tranter152, Charlie Vigurs152, Laura Wild152, Karen Austin152, Olivia Kelsall152 & Hannah Wood152 Royal Cornwall Hospital, Truro, UK Thomas Cornell153, Kate Ralph153, Sarah Bean153, Karen Burt153, Michael Spivey153, Carol Richards153 & Rachel Tedstone153 Watford General Hospital, Watford, UK Siobhain Carmody154, Xiaobei Zhao154, Valerie Page154, Mark Louie Guanco154, Elvira Hoxha154 & Camilla Zorloni154 Macclesfield District General Hospital, Macclesfield, UK Charlotte Dean155, Emma Jones155, Emma Carter155, Joshua Dunn155, Thomas Kong155, Mervin Mahenthran155, Chris Marsh155, Maureen Holland155, Natalie Keenan155, Mohamed Mahmoud155, Marc Lyons155, Joanne Bradley-Potts155, Helen Wassall155 & Meghan Young155 Royal Surrey County Hospital, Guildford, UK Paul Bradley156, Dorota Burda156, Sinead Donlon156, Lesley Harden156, Celia Harris156, Irving Mayangao156, Rugia Montaser156, Sheila Mtuwa156, Charles Piercy156, Eleanor Smith156, Sarah Stone156, Jerik Verula156, Helen Blackman156, Cheryl Marriott156, Natalia Michalak156, Ben Creagh-Brown156, Armorel Salberg156, Naomi Boyer156 & Veronika Pristopan156 Rotherham General Hospital, Rotherham, UK Victoria Maynard157, Rachel Walker157, Anil Hormis157, Dawn Collier157, Cheryl Graham157, Vicky Maynard157, Jake McCormick157 & Jake Warrington157 Craigavon Area Hospital, County Armagh, Northern Ireland Denise Cosgrove158, Denise McFarland158, Judith Ratcliffe158 & Rob Charnock158 King’s Mill Hospital, Nottingham, UK Inez Wynter159, Mandy Gill159, Jill Kirk159, Paul Paul159, Valli Ratnam159 & Sarah Shelton159 Dumfries and Galloway Royal Infirmary, Dumfries, UK Catherine Jardine160, Alasdair Hay160 & Dewi Williams160 Prince Charles Hospital, Merthyr Tydfil, UK Bethan Deacon161, Latha Durga161, Meg Hibbert161, Gareth Kennard-Holden161, Chrsitopher Woodford161, Carla Pothecary161, Lisa Roche161, Dariusz Tetla161, Kevin Agravante161 & Justyna Smeaton161 Ysbyty Gwynedd, Bangor, UK Alicia Price162, Alice Thomas162, Chris Thorpe162, Ellen Knights162 & Donna Ward162 Royal Preston Hospital, Preston, UK Shondipon Laha163, Mark Verlander163 & Alexandra Williams163 The Great Western Hospital, Swindon, UK Rachel Prout164, Helen Langton164, Malcolm Watters164, Charlotte Hunt164 & Catherine Novis164 Lincoln County Hospital, Lincoln, UK Sarwat Arif165, Amy Cunningham165, Claire Hewitt165, Julia Hindale165, Karen Jackson-Lawrence165, Sarah Shepardson165, Maryanne Wills165, Susie Butler165, Silivia Tavares165, Russell Barber165, Annette Hilldrith165 & Kelly Hubbard165 University Hospital of North Tees, Stockton on Tees, UK Dawn Egginton166, Michele Clark166, Sarah Purvis166, Simon Sinclair166 & Vicky Collins166 Glangwili General Hospital, Camarthen, UK Bethan Landeg167, Craig Sell167, Samantha Coetzee167, Alistair Gales167, Igor Otahal167, Becky Icke167, Meena Raj167, Caroline Williams167, Jill Williams167 & Lucy Hill167 Southend University Hospital, Westcliff-on-Sea, UK Abdul Kayani168, Bridgett Masunda168, Prisca Gondo168 & Nigara Atayeva168 Lister Hospital, Stevenage, UK Carina Cruz169 & Natalie Pattison169 Diana Princess of Wales Hospital, Grimsby, UK Caroline Burnett170, Jonathan Hatton170, Elaine Heeney170, Maria Newton170, Hassan Al-Moasseb170, Teresa Behan170, Jasmine Player170, Rachael Stead170, Atideb Mitra170 & Kirsty Nauyokas170 West Suffolk Hospital, Bury St Edmunds, UK Sally Humphreys171, Helen Cockerill171 & Ruth Tampsett171 Victoria Hospital, Kirkcaldy, UK Evgeniya Postovalova172, Tina Coventry172, Amanda McGregor172, Susan Fowler172, Mike Macmahon172, Patricia Cochrane172 & Sandra Pirie172 Calderdale Royal Hospital, Halifax, UK and Huddersfield Royal Infirmary, Huddersfield, UK Sarah Hanley173,174, Asifa Ali173,174, Megan Brady173,174, Sam Dale173,174, Annalisa Dance173,174, Lisa Gledhill173,174, Jill Greig173,174, Kathryn Hanson173,174, Kelly Holdroyd173,174, Marie Home173,174, Tahira Ishaq173,174, Diane Kelly173,174, Lear Matapure173,174, Deborah Melia173,174, Samantha Mellor173,174, Ekta Merwaha173,174, Tonicha Nortcliffe173,174, Lisa Shaw173,174, Ryan Shaw173,174, Tracy Wood173,174, Lee-Ann Bayo173,174, Miranda Usher173,174, Alison Wilson173,174, Ross Kitson173,174, Jez Pinnell173,174, Matthew Robinson173,174 & Kaitlin Boltwood173,174 Dorset County Hospital, Dorchester, UK Jenny Birch175, Laura Bough175, Rebecca Tutton175, Barbara Winter-Goodwin175, Josie Goodsell175, Kate Taylor175, Patricia Williams175, Sarah Williams175, Ashleigh Cave175 & James Rees175 Russell’s Hall Hospital, Dudley, UK Janet Imeson-Wood176, Jacqueline Smith176, Vishal Amin176, Komala Karthik176, Rizwana Kausar176, Elena Anastasescu176, Karen Reid176, Vikram Anumakonda176 & Ella Stoddart176 Royal United Hospital, Bath, UK Carrie Demetriou177, Charlotte Eckbad177, Lucy Howie177, Sarah Mitchard177, Lidia Ramos177, Katie White177, Sarah Hierons177, Fiona Kelly177, Alfredo Serrano-Ruiz177 & Gabrielle Evans177 St Mary’s Hospital, Newport, UK Liz Nicol178, Joy Wilkins178, Kim Hulacka178, Gabor Debreceni178, Alison Brown178 & Vikki Crickmore178 George Eliot Hospital NHS Trust, Nuneaton, UK Kay Hill179 & Thogulava Kannan179 Yeovil Hospital, Yeovil, UK Zenaida Dagutao180, Kate Beesley180, Alison Lewis180, Jess Perry180, Sherly Antony180, Sarah Board180, Clare Buckley180, Lucy Pippard180, Alfonso Tanate180, Diane Wood180, Agnieska Kubisz-Pudelko180 & Ayman Gouda180 Forth Valley Royal Hospital, Falkirk, UK Fiona Auld181, Joanne Donnachie181, Euan Murdoch181, Lynn Prentice181, Nikole Runciman181, Dhaneesha Senaratne181, Abigail Short181, Laura Sweeney181, Lesley Symon181, Anne Todd181, Patricia Turner181, Erin McCann181, Dario Salutous181, Ian Edmond181 & Lesley Whitelaw181 Frimley Park Hospital, Surrey, UK Harish Venkatesh182, Yvonne Bland182, Istvan Kajtor182, Lisa Kavanagh182, Karen Singler182 & George Linfield-Brown182 Chelsea & Westminster NHS Foundation Trust, London, UK Luke Stephen Prockter Moore183, Marcela Vizcaychipi183, Laura Martins183, Luke Moore183, Rhian Bull183 & Jaime Carungcong183 Queen Elizabeth the Queen Mother Hospital, Margate, UK Louise Allen184, Eva Beranova184, Alicia Knight184, Carly Price184, Sorrell Tilbey184, Sharon Turney184, Tracy Hazelton184, Gabriella Tutt184, Mansi Arora184, Salah Turki184, Emily Sinfield184, Joanne Deery184 & Hazel Ramos184 Royal Brompton Hospital, London, UK Daniele Cristiano185, Natalie Dormand185, Zohreh Farzad185, Mahitha Gummadi185, Sara Salmi185, Geraldine Sloane185, Mathew Varghese185, Vicky Thwaites185, Brijesh Patel185, Liyanage Kamal185 & Anelise Catelan Zborowski185 Darent Valley Hospital, Dartford, UK Ryan Coe186, Madeleine Anderson186, Jane Beadle186, Charlotte Coates186, Katy Collins186, Maria Crowley186, Laura Johnson186, Laura King186, Remi Paramsothy186, Janet Sargeant186, Pedro Silva186, Carmel Stuart186, June Taylor186, David Tyl186, Phillipa Wakefield186, Charlotte Kamundi186, Olumide Olufuwa186, Zakaulla Belagodu186, Anca Gherman186 & Naomi Oakley186 University Hospital Crosshouse, Kilmarnock, UK John Allan187, Tim Geary187, Alistair Meikle187, Peter O’Brien187, Stephen Wood187, Andrew Clark187 & Gordon Houston187 University Hospital Wishaw, Wishaw, UK Karen Black188, Michelle Clarkson188, Stuart D’Sylva188, Alan Morrison188, Kathryn Norman188, Margaret Taylor188, Suzanne Clements188, Catriona Cohrane188, Nora Gonzalez188, Dominic Strachan188, Claire Beith188 & Kirsten Moar188 University College Dublin, St Vincent’s University Hospital, Dublin, Ireland Lorna Murphy189, Michelle Smythe189, Alistair Nichol189 & Kathy Brickell189 The Queen Elizabeth Hospital, King’s Lynn, UK Inthakab Ali Mohamed Ali190, Karen Beaumont190, Mohamed Elsaadany190, Kay Fernandes190, Sameena Mohamed Ally190, Harini Rangarajan190, Varun Sarathy190, Sivarupan Selvanayagam190, Dave Vedage190, Matthew White190, Zoe Coton190, Aricsa Joshy190, Mark Blunt190 & Hollie Curgenven190 Walsall Manor Hospital, Walsall, UK Liam Botfield191, Catherine Dexter191, Aditya Kuravi191, Joanne Butler191, Robert Chadwick191, Poonam Ranga191, Lisa Richardson191, Emma Virgilio191, Maddiha Anwer191, Atul Garg191, Donna Botfield191 & Xana Marriott191 Princess Royal Hospital, Brighton, UK Keely Stewart192, Dee Mullan192, Claire Phillips192, Jane Gaylard192, Justyna Nowak192 & Denise Skinner192 Barnsley Hospital, Barnsley, UK Sian Jones193, Rikki Crawley193, Abigail Crew193, Mishell Cunningham193, Allison Daniels193, Laura Harrison193, Susan Hope193, Nicola Lancaster193, Jamie Matthews193, Gemma Wray193, Alice Nicholson193, Ken Inweregbu193, Sarah Cutts193 & Katharine Miller193 Warrington General Hospital, Warrington, UK Ailbhe Brady194, Rebekah Chan194, Shane McIvor194, Helena Prady194, Bijoy Mathew194, Jeff Little194 & Tim Furniss194 Royal Victoria Hospital, Belfast, NI Chris Wright195, Bernadette King195, Christopher Wasson195, Aisling O’Neill195, Christine Turley195, Peter McGuigan195, Erin Collins195, Stephanie Finn195, Jackie Green195, Julie McAuley195, Abitha Nair195, Charlotte Quinn195, Suzanne Tauro195, Kathryn Ward195, Michael McGinlay195 & Kiran Reddy195 Royal Hallamshire Hospital and Northern General Hospital, Sheffield, UK Norfaizan Ahmad196, Samantha Anderson196, Joann Barker196, Kris Bauchmuller196, Kathryn Birchall196, Sarah Bird196, Kay Cawthron196, Luke Chetam196, Joby Cole196, Ben Donne196, David Foote196, Amber Ford196, Helena Hanratty196, Kate Harrington196, Lisa Hesseldon196, Kay Housley196, Yvonne Jackson196, Claire Jarman196, Faith Kibutu196, Becky Lenagh196, Irene Macharia196, Shamiso Masuko196, Leanne Milner196, Helen Newell196, Lorenza Nwafor196, Simon Oxspring196, Patrick Phillips196, Ajay Raithatha196, Sarah Rowland-Jones196, Jacqui Smith196, Roger Thompson196, Helen Trower196, Sara Walker196, James Watson196, Matthew Wiles196, Alison Lye196, Jayne Willson196, Gary Mills196, Sansha Harris196 & Eleanor Hartill196 Harefield Hospital, London, UK Anthony Barron197, Ciara Collins197, Sundeep Kaul197, Claire Nolan197, Oliver Polgar197, Claire Prendergast197, Paula Rogers197, Rajvinder Shokkar197, Meriel Woodruff197, Kanta Mahay197, Vicky Thwaites197, Anna Reed197, Hayley Meyrick197, Heather Passmore197 & James Farwell197 Cumberland Infirmary, Carlisle, UK Alison Brown198, Susan O’Connell198, Jane Gregory198, Luigi Barberis198, Rosemary Harper198, Tim Smith198 & Diane Armstrong198 Eastbourne District General Hospital, East Sussex, UK and Conquest Hospital, East Sussex, UK Angie Bowey199,200, Anne Cowley199,200, Andrew Corner199,200, Judith Highgate199,200, Claire Rutherfurd199,200, Jo-Anne Taylor199,200, Sarah Goodwin199,200 & Claire Rutherford199,200 Salisbury District Hospital, Salisbury, UK Beena Eapen201, Fiona Trim201 & Phil Donnison201 Airedale General Hospital, Keighley, UK Lisa Armstrong202, Hayley Bates202, Emma Dooks202, Fiona Farquhar202, Amy Kitching202, Chantal McParland202, Sophie Packham202 & Brigid Hairsine202 Leicester Royal Infirmary, Leicester, UK Anand Patil203, Premetie Andreou203, Dawn Hales203, Megha Mathews203, Rekha Patel203, Peter Barry203, Neil Flint203, Jessica Hailstone203, Navneet Ghuman203, Bethany Leonard203 & Rachel Lees203 Peterborough City Hospital, Peterborough, UK and Hinchingbrooke Hospital, Huntingdon, UK Deborah Butcher204,205, Katy Leng204,205, Nicola Butterworth-Cowin204,205 & Susie O’Sullivan204,205 Colchester General Hospital, Colchester, UK Alison Ghosh206 & Emma Williams206 Princess Royal Hospital, Telford and Royal Shrewsbury Hospital, Shrewsbury, UK Colene Adams207, Anita Agasou207, Tracie Arden207, Mandy Beekes207, Amy Bowes207, Pauline Boyle207, Heather Button207, Mandy Carnahan207, Anne Carter207, Danielle Childs207, Jane Gaylard207, Fran Hurford207, Yasmin Hussain207, Ayesha Javaid207, James Jones207, Michael Leigh207, Terry Martin207, Helen Millward207, Nichola Motherwell207, Dee Mullan207, Julie Newman207, Rachel Rikunenko207, Jo Stickley207, Julie Summers207, Louise Ting207, Helen Tivenan207, Denise Donaldson207, Nigel Capps207, Emily Cale207, Sanal Jose207, Wendy Osbourne207, Susie Pajak207, Jayne Rankin207 & Louise Tonks207 University Hospital Monklands, Airdrie, UK Tracy Baird208, Margaret Harkins208, Jim Ruddy208 & Joe West208 Wrexham Maelor Hospital, Wrexham, Wales Joseph Duffield209, Lewis Mallon209, Oliver Smith209, Sara Smuts209, Andy Campbell209, Cate Davies209, Sarah Davies209, Rachel Hughes209, Lisa Jobes209, Victoria Whitehead209 & Clare Watkins209 Royal Hospital for Children, Glasgow, UK Fiona Bowman27, Barry Milligan27, Colin Begg27 & Liane McPherson27 New Cross Hospital, Wolverhampton, UK Stella Metherell210, Nichola Harris210, Victoria Lake210, Elizabeth Radford210, Andy Smallwood210, Shameer Gopal210 & Katherine Vassell210 University Hospital Hairmyres, East Kilbride, UK Dina Bell211, Rosalind Boyle211, Katie Douglas211, Lynn Glass211, Liz Lennon211, Austin Rattray211, Claire Beith211 & Emma Lee211 Warwick Hospital, Warwick, UK Danielle Jones212, Penny Parsons212, Ben Attwood212, Paul Jefferson212, Mohan Ranganathan212, Inderjit Atwal212, Bridget Campbell212, Angela Day212 & Camilla Stagg212 Sandwell General Hospital and City Hospital, Birmingham, UK Emma Haynes213, Cecilia Ahmed213, Sarah Clamp213, Julie Colley213, Risna Haq213, Anne Hayes213, Sibet Joseph213, Zahira Maqsood213, Samia Hussain213, Jonathan Hulme213, Patience Domingos213, Rita Kumar213, Manjit Purewal213 & Becky Taylor213 Royal Manchester Children’s Hospital, Manchester, UK Lara Bunni214, Monica Latif214, Claire Jennings214, Shilu Jose214, Rebecca Marshall214, Aleksandra Metryka214 & Gayathri Subramanian214 Gloucestershire Royal Hospital, Gloucester, UK Adam Burgoyne215, Susan O’Connell215, Amanda Tyler215, Joanne Waldron215, Paula Hilltout215 & Jayne Evitts215 University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK Geraldine Ward216, Pamela Bremmer216, Carl Hawkins216, Sophie Jackman216 & Michal Ogorek216 Torbay Hospital, Torquay, UK Kylie Ashby217, Lorraine Thornton217, Pauline Mercer217, Matthew Halkes217 & Adam Revill217 Pilgrim Hospital, Lincoln, UK Bryony Saint218, Jo Fletcher218, Kimberley Netherton218, Manish Chablani218, Amy Kirkby218, Amanda Roper218 & Kinga Szymiczek218 Prince Philip Hospital, Lianelli, UK Isobel Sutherland219, Linda O’Brien219, Igor Otahal219, Joanne Connell219, Kim Davies219, Tracy Lewis219, Zohra Omar219 & Emma Perkins219 Princess of Wales Hospital, Llantrisant, UK Lisa Roche220, Sonia Sathe220 & Ellie Davies220 Northampton General Hospital NHS Trust, Northampton, UK Alex Lyon221, Isheunesu Mapfunde221, Charlotte Willis221, Rachael Hitchcock221, Kathryn Hall221 & Christopher King221 The Christie NHS Foundation Trust, Manchester, UK Andrew Fagan222, Roonak Nazari222, Lucy Worsley222, Suzanne Allibone222, Vidya Kasipandian222, Amit Patel222, Parisa Cutting222, Roman Genetu222, Ainhi Mac222, Anthony Murphy222, Sinead Ward222 & Fatima Butt222 James Paget University Hospital NHS Trust, Great Yarmouth, UK Amanda Ayers223, Wendy Harrison223, Katherine Mackintosh223 & Julie North223 Birmingham Children’s Hospital, Birmingham, UK Lydia Ashton224, Rehana Bi224, Samantha Owen224, Helen Winmill224 & Barney Scholefield224 Withybush General Hospital, Pembrokeshire, Wales Hannah Blowing225, Erin Williams225, Michaela Duskova225, Michelle Edwards225, Alun Rees225, Helen Thomas225, Rachel Hughes225, Igor Otahal225, Jolene Brooks225, Janet Phipps225 & Suzanne Brooks225 Northwick Park Hospital, London, UK Catherine Dennis226, Vicki Parris226, Sinduya Srikaran226, Anisha Sukha226, Alistair McGregor226 & Gerlynn Tiongson226 North Devon District Hospital, Barnstaple, UK Katie Adams227, Benedict Andrew227, Adam Brayne227, Sasha Carter227, Louise Findlay227, Emma Fisher227, Peter Jackson227, Duncan Kaye227, Juliet Parkin227, Victoria Tuckey227, Jane Hunt227, Nicholas Love227, Lynne van Koutrick227 & Ashley Hanson227 Article Scunthorpe General Hospital, Scunthorpe, UK Kathy Dent228, Elizabeth Horsley228, Sandra Pearson228, Sue Spencer228, Dorothy Hutchinson228, Jasmine Player228, Dorota Potoczna228, Muhammad Nauman Akhtar228, Lisa-Jayne Cottam228, Kirsty Nauyokas228 & Jack Sanders228 Royal Free Hospital, London, UK Sara Mingo Garcia229, Glykeria Pakou229, Cynthia Diaba229, Helder Filipe229, Lincy John229, Amitaa Maharajh229, Mark de Neef229, Daniel Martin229, Christine Eastgate229 & Poh Choo Teoh229 Raigmore Hospital, Inverness, UK Fiona Barrett230, Clare Bradley230, Avril Donaldson230, Mairi Mascarenhas230, Marianne O’Hara230, Laura Okeefe230, Noreen Clarke230, Jonathan Whiteside230, Rachael Campbell230, Joanna Matheson230, Deborah McDonald230 & Donna Patience230 West Cumberland Hospital, Whitehaven, UK Polly Rice231, Tim Smith231, Melanie Clapham231, Rachel Mutch231, Luigi Barberis231, Rosemary Harper231, Hannah Craig231 & Una Poultney231 Furness General Hospital, Barrow-in-Furness, UK Karen Burns232 & Andrew Higham232 Liverpool Heart and Chest Hospital, Liverpool, UK Sophie Twiss233, Janet Barton233, Linsha George233, Clare Harrop233, Sherly Mathew233 & David Justin Wright233 Scarborough General Hospital, Scarborough, UK Rachel Harrison234, Jordan Toohie234, Ben Chandler234, Alison Turnbull234, Janine Mallinson234 & Kerry Elliott234 Bronglais General Hospital, Aberystwyth, UK Rebecca Wolf-Roberts235, Helen Tench235, Igor Otahal235, Maria Hobrok235, Ronda Loosley235, Heather McGuinness235 & Tanya Sims235 Alder Hey Children’s Hospital, Liverpool, UK Deborah Afolabi236, Kathryn Sian Allison236, Taya Anderson236, Rachael Dore236, Dawn Jones236, Naomi Rogers236, Paula Saunderson236, Jennifer Whitbread236, Laura O’Malley236, Laura Rad236 & Daniel Hawcutt236 Borders General Hospital, Melrose, UK Jonathan Aldridge237, Melanie Tolson237 & Sweyn Garrioch237 Leighton Hospital, Cheshire, UK Joanne Tomlinson238 & Michael Grosdenier238 Kent & Canterbury Hospital, Canterbury, UK David Loader239, Ritoo Kapoor239 & Gemma Hector239 Harrogate and District NHS Foundation Trust, Harrogate, UK Joslan Scherewode240, Chunda Sri-Chandana240, Lorraine Stephenson240 & Sarah Marsh240 The Royal Marsden Hospital, London, UK Arnold Dela Rosa241, Shaman Jhanji241, Thomas Bemand241, Ryan Howle241, Ravishankar Rao Baikady241, Benjamin Thomas241, Ethel Black241 & Kate Tatham241 Ealing Hospital, Southall, UK Sambasivarao Gurram242, Ekaterina Watson242, Vicki Parris242, Sheena Quaid242 & Alistair McGregor242 St John’s Hospital Livingston, Livingston, UK Anne Saunderson243, Rachel O’Brien243, Sam Moultrie243, Jen Service243, Clare Cheyne243, Miranda Odam243 & Alison Wiliams243 Wexham Park Hospital, Slough, UK Nicky Barnes244, Peter Csabi244, Joana Da Rocha244 & Louika Glynou244 Sheffield Children’s Hospital, Sheffield, UK Amy Huffenberger245, Jade Bryant245, Amy Pickard245, Nicholas Roe245, Arianna Bellini245, Anton Mayer245, Amy Burrow245, Natalie Colley245, Jayne Evans245, Alex Howlett245 & Zeinab Khalifeh245 Homerton University Hospital Foundation NHS Trust, London UK Jerldine Pryce246, Claire Gorman246, Amy Easthope246, Rebecca Brady246, Elizabeth Timlick246, Pierre Antoine246 & Abhinhav Gupta246 National Hospital for Neurology and Neurosurgery, London, UK John Hardy247, Henry Houlden247, Eleanor Moncur247, Arianna Tucci247, Eamon Raith247, Ambreen Tariq247 & David Brealey247 The Royal Alexandra Children’s Hospital, Brighton, UK Emma Tagliavini248, Becky Ramsay248, Katy Fidler248, Kevin Donnelly248 & Rebecca Hollis248 Golden Jubilee National Hospital, Clydebank, UK Jocelyn Barr249, Elizabeth Boyd249, Val Irvine249, Ben Shelley249, Julie Buckley249, Charlene Hamilton249 & Kathryn Valdeavella249 49NIHR Clinical Research Network (CRN), North West London Core Team, Hammersmith Hospital, London, UK. 50Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 51Biostatistics Group, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. 52Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. 53Guys and St Thomas’ Hospital, London, UK. 54James Cook University Hospital, Middlesbrough, UK. 55Barts Health NHS Trust, London, UK. 56Royal Stoke University Hospital, Stoke-on-Trent, UK. 57North Middlesex University Hospital NHS Trust, London, UK. 58King’s College Hospital, London, UK. 59Charing Cross Hospital, St Mary’s Hospital and Hammersmith Hospital, London, UK. 60The Royal Liverpool University Hospital, Liverpool, UK. 61John Radcliffe Hospital, Oxford, UK. 62Addenbrooke’s Hospital, Cambridge, UK. 63Nottingham University Hospital, Nottingham, UK. 64St George’s Hospital, London, UK. 65BHRUT (Barking Havering)—Queens Hospital and King George Hospital, Ilford, UK. 66Royal Infirmary of Edinburgh, Edinburgh, UK. 67Kingston Hospital, London, UK. 68Queen Alexandra Hospital, Portsmouth, UK. 69Royal Gwent Hospital, Newport, UK. 70Royal Blackburn Teaching Hospital, Blackburn, UK. 71Stepping Hill Hospital, Stockport, UK. 72Northumbria Healthcare NHS Foundation Trust, North Shields, UK. 73Countess of Chester Hospital, Chester, UK. 74Pinderfields General Hospital, Wakefield, UK. 75Ninewells Hospital, Dundee, UK. 76Croydon University Hospital, Croydon, UK. 77Morriston Hospital, Swansea, UK. 78Queen Elizabeth University Hospital, Glasgow, UK. 79Broomfield Hospital, Chelmsford, UK. 80Heartlands Hospital, Birmingham, UK. 81Royal Sussex County Hospital, Brighton, UK. 82York Hospital, York, UK. 83Queen Elizabeth Hospital, Birmingham, UK. 84Royal Glamorgan Hospital, Pontyclun, UK. 85Barnet Hospital, London, UK. 86Wythenshawe Hospital, Manchester, UK. 87Medway Maritime Hospital, Gillingham, UK. 88Royal Berkshire NHS Foundation Trust, Reading, UK. 89Whiston Hospital, Prescot, UK. 90The Royal Oldham Hospital, Manchester, UK. 91Chesterfield Royal Hospital Foundation Trust, Chesterfield, UK. 92Aberdeen Royal Infirmary, Aberdeen, UK. 93Royal Devon and Exeter Hospital, Exeter, UK. 94Glasgow Royal Infirmary, Glasgow, UK. 95Blackpool Victoria Hospital, Blackpool, UK. 96Southampton General Hospital, Southampton, UK. 97Ashford and St Peter’s Hospital, Chertsey, UK. 98Derriford Hospital, Plymouth, UK. 99East Surrey Hospital, Redhill, UK. 100Poole Hospital, Poole, UK. 101Royal Alexandra Hospital, Paisley, UK. 102St James’s University Hospital and Leeds General Infirmary, Leeds, UK. 103Bedford Hospital, Bedford, UK. 104Southport and Formby District General Hospital, Ormskirk, UK. 105The Tunbridge Wells Hospital and Maidstone Hospital, Kent, UK. 106Queen Elizabeth Hospital, Woolwich, London, UK. 107North Manchester General Hospital, Manchester, UK. 108Royal Victoria Infirmary, Newcastle Upon Tyne, UK. 109Hull Royal Infirmary, Hull, UK. 110Manchester Royal Infirmary, Manchester, UK. 111Royal Derby Hospital, Derby, UK. 112Aintree University Hospital, Liverpool, UK. 113Fairfield General Hospital, Bury, UK. 114Norfolk and Norwich University Hospital (NNUH), Norwich, UK. 115Milton Keynes University Hospital, Milton Keynes, UK. 116Good Hope Hospital, Birmingham, UK. 117Queen Elizabeth Hospital Gateshead, Gateshead, UK. 118Royal Bolton Hospital, Bolton, UK. 119Tameside General Hospital, Ashton Under Lyne, UK. 120Salford Royal Hospital, Manchester, UK. 121Great Ormond St Hospital and UCL Great Ormond St Institute of Child Health NIHR Biomedical Research Centre, London, UK. 122Southmead Hospital, Bristol, UK. 123William Harvey Hospital, Ashford, UK. 124Arrowe Park Hospital, Wirral, UK. 125Royal Hampshire County Hospital, Winchester, UK. 126Bradford Royal Infirmary, Bradford, UK. 127Glan Clwyd Hospital, Bodelwyddan, UK. 128Royal Bournemouth Hospital, Bournemouth, UK. 129Bristol Royal Infirmary, Bristol, UK. 130University Hospital North Durham, Darlington, UK. 131Darlington Memorial Hospital, Darlington, UK. 132Basildon Hospital, Basildon, UK. 133University College Hospital, London, UK. 134Whittington Hospital, London, UK. 135Western General Hospital, Edinburgh, UK. 136Ipswich Hospital, Ipswich, UK. 137Hereford County Hospital, Hereford, UK. 138Sunderland Royal Hospital, Sunderland, UK. 139Queens Hospital Burton, Burton-On-Trent, UK. 140Musgrove Park Hospital, Taunton, UK. 141The Royal Papworth Hospital, Cambridge, UK. 142University Hospital Lewisham, London, UK. 143The Princess Alexandra Hospital, Harlow, UK. 144University Hospital of Wales, Cardiff, UK. 145West Middlesex Hospital, Isleworth, UK. 146Royal Albert Edward Infirmary, Wigan, UK. 147Stoke Mandeville Hospital, Aylesbury, UK. 148Royal Lancaster Infirmary, Lancaster, UK. 149Basingstoke and North Hampshire Hospital, Basingstoke, UK. 150Worthing Hospital, Worthing, UK. 151St Richard’s Hospital, Chichester, UK. 152The Alexandra Hospital, Redditch and Worcester Royal Hospital, Worcester, UK. 153Royal Cornwall Hospital, Truro, UK. 154Watford General Hospital, Watford, UK. 155Macclesfield District General Hospital, Macclesfield, UK. 156Royal Surrey County Hospital, Guildford, UK. 157Rotherham General Hospital, Rotherham, UK. 158Craigavon Area Hospital, Portadown, UK. 159King’s Mill Hospital, Nottingham, UK. 160Dumfries and Galloway Royal Infirmary, Dumfries, UK. 161Prince Charles Hospital, Merthyr Tydfil, UK. 162Ysbyty Gwynedd, Bangor, UK. 163Royal Preston Hospital, Preston, UK. 164The Great Western Hospital, Swindon, UK. 165Lincoln County Hospital, Lincoln, UK. 166University Hospital of North Tees, Stockton on Tees, UK. 167Glangwili General Hospital, Camarthen, UK. 168Southend University Hospital, Westcliff-on-Sea, UK. 169Lister Hospital, Stevenage, UK. 170Diana Princess of Wales Hospital, Grimsby, UK. 171West Suffolk Hospital, Bury St Edmunds, UK. 172Victoria Hospital, Kirkcaldy, UK. 173Calderdale Royal Hospital, Halifax, UK. 174Huddersfield Royal Infirmary, Huddersfield, UK. 175Dorset County Hospital, Dorchester, UK. 176Russell’s Hall Hospital, Dudley, UK. 177Royal United Hospital, Bath, UK. 178St Mary’s Hospital, Newport, UK. 179George Eliot Hospital NHS Trust, Nuneaton, UK. 180Yeovil Hospital, Yeovil, UK. 181Forth Valley Royal Hospital, Falkirk, UK. 182Frimley Park Hospital, Camberley, UK. 183Chelsea & Westminster NHS Foundation Trust, London, UK. 184Queen Elizabeth the Queen Mother Hospital, Margate, UK. 185Royal Brompton Hospital, London, UK. 186Darent Valley Hospital, Dartford, UK. 187University Hospital Crosshouse, Kilmarnock, UK. 188University Hospital Wishaw, Wishaw, UK. 189University College Dublin, St Vincent’s University Hospital, Dublin, Ireland. 190The Queen Elizabeth Hospital, King’s Lynn, UK. 191Walsall Manor Hospital, Walsall, UK. 192Princess Royal Hospital, Brighton, UK. 193Barnsley Hospital, Barnsley, UK. 194Warrington General Hospital, Warrington, UK. 195Royal Victoria Hospital, Belfast, UK. 196Royal Hallamshire Hospital and Northern General Hospital, Sheffield, UK. 197Harefield Hospital, London, UK. 198Cumberland Infirmary, Carlisle, UK. 199Eastbourne District General Hospital, Eastbourne, UK. 200Conquest Hospital, Saint Leonards-on-Sea, UK. 201Salisbury District Hospital, Salisbury, UK. 202Airedale General Hospital, Keighley, UK. 203Leicester Royal Infirmary, Leicester, UK. 204Peterborough City Hospital, Peterborough, UK. 205Hinchingbrooke Hospital, Huntingdon, UK. 206Colchester General Hospital, Colchester, UK. 207Princess Royal Hospital, Telford and Royal Shrewsbury Hospital, Shrewsbury, UK. 208University Hospital Monklands, Airdrie, UK. 209Wrexham Maelor Hospital, Wrexham, UK. 210New Cross Hospital, Wolverhampton, UK. 211University Hospital Hairmyres, East Kilbride, UK. 212Warwick Hospital, Warwick, UK. 213Sandwell General Hospital and City Hospital, Birmingham, UK. 214Royal Manchester Children’s Hospital, Manchester, UK. 215Gloucestershire Royal Hospital, Gloucester, UK. 216University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK. 217Torbay Hospital, Torquay, UK. 218Pilgrim Hospital, Lincoln, UK. 219Prince Philip Hospital, Lianelli, UK. 220Princess of Wales Hospital, Llantrisant, UK. 221Northampton General Hospital NHS Trust, Northampton, UK. 222The Christie NHS Foundation Trust, Manchester, UK. 223James Paget University Hospital NHS Trust, Great Yarmouth, UK. 224Birmingham Children’s Hospital, Birmingham, UK. 225Withybush General Hospital, Haverfordwest, UK. 226Northwick Park Hospital, London, UK. 227North Devon District Hospital, Barnstaple, UK. 228Scunthorpe General Hospital, Scunthorpe, UK. 229Royal Free Hospital, London, UK. 230Raigmore Hospital, Inverness, UK. 231West Cumberland Hospital, Whitehaven, UK. 232Furness General Hospital, Barrow-in-Furness, UK. 233Liverpool Heart and Chest Hospital, Liverpool, UK. 234Scarborough General Hospital, Scarborough, UK. 235Bronglais General Hospital, Aberystwyth, UK. 236Alder Hey Children’s Hospital, Liverpool, UK. 237Borders General Hospital, Melrose, UK. 238Leighton Hospital, Crewe, UK. 239Kent & Canterbury Hospital, Canterbury, UK. 240Harrogate and District NHS Foundation Trust, Harrogate, UK. 241The Royal Marsden Hospital, London, UK. 242Ealing Hospital, Southall, UK. 243St John’s Hospital Livingston, Livingston, UK. 244Wexham Park Hospital, Slough, UK. 245Sheffield Children’s Hospital, Sheffield, UK. 246Homerton University Hospital Foundation NHS Trust, London, UK. 247National Hospital for Neurology and Neurosurgery, London, UK. 248The Royal Alexandra Children’s Hospital, Brighton, UK. 249Golden Jubilee National Hospital, Clydebank, UK. SCOURGE Consortium Javier Abellan250,251, René Acosta-Isaac252, Jose María Aguado253,254,255,256, Carlos Aguilar257, Sergio Aguilera-Albesa258,259, Abdolah Ahmadi Sabbagh260, Jorge Alba261, Sergiu Albu262,263,264, Karla A. M. Alcalá-Gallardo265, Julia Alcoba-Florez266, Sergio Alcolea Batres267, Holmes Rafael Algarin-Lara268,269, Virginia Almadana270, Julia Almeida271,272,273,274, Berta Almoguera37,275, María R. Alonso276, Nuria Alvarez276, Yady Álvarez-Benítez268,269, Felipe Álvarez-Navia277,278, Rodolfo Alvarez-Sala Walther267, Álvaro Andreu-Bernabeu255,279, Maria Rosa Antonijoan280, Eunate Arana-Arri281,282, Carlos Aranda283,284, Celso Arango255,279,285, Carolina Araque286,287, Nathalia K. Araujo288, Izabel M. T. Araujo289, Ana C. Arcanjo290,291,292, Ana Arnaiz33,34,35, Francisco Arnalich Fernández293, María J. Arranz294, José Ramon Arribas Lopez293, Maria-Jesus Artiga295, Yubelly Avello-Malaver296, Carmen Ayuso37,275, Ana Margarita Baldión-Elorza296, Belén Ballina Martín260, Raúl C. Baptista-Rosas297,298,299, Andrea Barranco-Díaz269, María Barreda-Sánchez300,301, Viviana Barrera-Penagos296, Moncef Belhassen-Garcia278,302, Enrique Bernal300, David Bernal-Bello303, Joao F. Bezerra304, Marcos A. C. Bezerra305, Natalia Blanca-López306, Rafael Blancas307, Lucía Boix-Palop308, Alberto Borobia309, Elsa Bravo310, María Brion311,312, Óscar Brochado-Kith256,313, Ramón Brugada312,314,315,316, Matilde Bustos317, Alfonso Cabello318, Juan J. Caceres-Agra319, Esther Calbo320, Enrique J. Calderón321,322,323, Shirley Camacho324, Marcela C. Campos290, Yolanda Cañadas284, Cristina Carbonell277,278, Servando Cardona-Huerta36, Antonio Augusto F. Carioca325, Maria Sanchez Carpintero283,284, Carlos Carpio Segura267, Thássia M. T. Carratto326, José Antonio Carrillo-Avila327, Maria C. C. Carvalho328, Carlos Casasnovas37,329,330, Luis Castano37,281,331,332,333, Carlos F. Castaño283,284, Jose E. Castelao334, Aranzazu Castellano Candalija335, María A. Castillo324, Francisco C. Ceballos313, Jessica G. Chaux287, Walter G. Chaves-Santiago287,336, Sylena Chiquillo-Gómez268,269, Marco A. Cid-Lopez265, Oscar Cienfuegos-Jimenez36, Rosa Conde-Vicente337, M. Lourdes Cordero-Lorenzana338, Dolores Corella339,340, Almudena Corrales30,31, Jose L. Cortes-Sanchez36,341, Marta Corton37,275, Tatiana X. Costa342, Raquel Cruz37,44,45,343, Marina S. Cruz288, Luisa Cuesta344, Gabriela C. R. Cunha345, Gabriela V. da Silva289, David Dalmau320,346, Raquel C. S. Dantas-Komatsu288, M. Teresa Darnaude347, Raimundo de Andrés348, Jéssica N. G. de Araújo349, Carmen de Juan350, Juan De la Cruz Troca322,351,352, Carmen de la Horra323, Ana B. de la Hoz281, Alba De Martino-Rodríguez353,354, Julianna Lys de Sousa Alves Neri355, Victor del Campo-Pérez356, Juan Delgado-Cuesta357, Covadonga M. Diaz-Caneja255,279,285, Anderson Díaz-Pérez269, Aranzazu Diaz de Bustamante347, Beatriz Dietl320, Silvia Diz-de Almeida37,44, Manoella do Monte Alves358,359, Elena Domínguez-Garrido360, Katiusse A. dos Santos328, Alice M. Duarte289, Jose Echave-Sustaeta361, Rocío Eiros362, César O. Enciso-Olivera286,287, Gabriela Escudero363, Pedro Pablo España364, Gladys Mercedes Estigarribia Sanabria365, María Carmen Fariñas33,34,35, Marianne R. Fernandes366,367, Ramón Fernández33,368, Lidia Fernandez-Caballero37,275, Ana Fernández-Cruz369, María J. Fernandez-Nestosa370, Uxía Fernández-Robelo371, Amanda Fernández-Rodríguez256,313, Marta Fernández-Sampedro33,34,35, Ruth Fernández-Sánchez37,275, Tania Fernández-Villa372, Silvia Fernández Ferrero260, Yolanda Fernández Martínez260, Carmen Fernéndez Capitán335, Patricia Flores-Pérez373, Vicente Friaza322,323, Lácides Fuenmayor-Hernández269, Marta Fuertes Núñez260, Victoria Fumadó374, Ignacio Gadea375, Lidia Gagliardi283,284, Manuela Gago-Domínguez45,46, Natalia Gallego38, Cristina Galoppo376, Inés García37,275, Mercedes García283,284, Leticia García283,284, Carlos Garcia-Cerrada37,250,251, Aitor García-de-Vicuña281,331, Josefina Garcia-García300, Irene García-García309, Carmen García-Ibarbia33,34,35, Andrés C. García-Montero377, Ana García-Soidán378, Elisa García-Vázquez300, María Carmen García Torrejón251,379, Emiliano Garza-Frias36, Angela Gentile376, Belén Gil-Fournier380, Javier Gómez-Arrue353,354, Mario Gómez-Duque287,336, Luis Gómez Carrera267, María Gómez García343, Ángela Gómez Sacristán381, Anna González-Neira276, Javier González-Peñas255,279,285, Manuel Gonzalez-Sagrado337, Beatriz González Álvarez353,354, Fernan Gonzalez Bernaldo de Quirós382, Hugo Gonzalo Benito383, Oscar Gorgojo-Galindo384, Miguel Górgolas318, Florencia Guaragna376, Genilson P. Guegel385, Beatriz Guillen-Guio30, Encarna Guillen-Navarro300,386,387,388, Pablo Guisado-Vasco361, Juan F. Gutiérrez-Bautista389, Luz D. Gutierrez-Castañeda287,390, Sarah Heili-Frades391, Estefania Hernandez392, Luis D. Hernandez-Ortega299,393, Guillermo Hernández-Pérez277, Rebeca Hernández-Vaquero394, Cristina Hernández Moro260, Belen Herraez276, M. Teresa Herranz300, María Herrera283,284, María José Herrero395,396, Antonio Herrero-Gonzalez397, Juan P. Horcajada256,263,398,399,400, Natale Imaz-Ayo281, Maider Intxausti-Urrutibeaskoa401, María Íñiguez402, Rafael H. Jacomo403, Rubén Jara300, Perez Maria Jazmin376, Ángel Jiménez283,284, Pilar Jiménez389, Ignacio Jiménez-Alfaro404, María A. Jimenez-Sousa256,313, Iolanda Jordan322,405,406, Rocío Laguna-Goya407,408, Daniel Laorden267, María Lasa-Lazaro407,408, María Claudia Lattig324,409, Ailen Lauriente376, Anabel Liger Borja410, Lucía Llanos411, Amparo López-Bernús277,278, Esther Lopez-Garcia322,351,352,412, Rosario Lopez-Rodriguez37,275, Miguel A. López-Ruz413,414,415, Eduardo López Granados37,416,417, Leonardo Lorente418, José E. Lozano419, María Lozano-Espinosa410, Andre D. Luchessi420, Ignacio Mahillo31,421,422, Esther Mancebo407,408, Carmen Mar364, Cristina Marcelo Calvo335, Miguel Marcos277,278, Alba Marcos-Delgado423, Alicia Marín Candon309, Pablo Mariscal Aguilar267, María M. Martín424, María Dolores Martín425, Vicente Martín322,423, Marta Martin-Fernandez426, Caridad Martín-López410, José-Ángel Martín-Oterino277,278, Laura Martin-Pedraza306, María Martín-Vicente313, Amalia Martinez427, Ricardo Martínez392, Juan José Martínez37,330, Silvia Martínez33,35, Eleno Martínez-Aquino428, Óscar Martínez-González307, Iciar Martinez-Lopez429,430, Oscar Martinez-Nieto296,409, Pedro Martinez-Paz383, Angel Martinez-Perez431, Andrea Martínez-Ramas37,275, Michel F. Martinez-Resendez36, Violeta Martínez Robles260, Laura Marzal37,275, Juliana F. Mazzeu432,433,434, Jeane F. P. Medeiros288, Kelliane A. Medeiros435,436, Francisco J. Medrano321,322,323, Xose M. Meijome437,438, Natalia Mejuto-Montero439, Ana Méndez-Echevarria293, Humberto Mendoza Charris269,310, Eleuterio Merayo Macías440, Fátima Mercadillo441, Arieh R. Mercado-Sesma299,393, Pablo Minguez37,275, Antonio J. J. Molina322,423, Elena Molina-Roldán442, Juan José Montoya392, Vitor M. S. Moraes326, Patricia Moreira-Escriche350, Xenia Morelos-Arnedo269,310, Antonio Moreno-Docón300, Junior Moreno-Escalante269, Victor Moreno Cuerda250,251, Alberto Moreno Fernández335, Rubén Morilla323,443, Patricia Muñoz García31,255,444, Pablo Neira376, Julian Nevado37,38,445, Israel Nieto-Gañán378, Joana F. R. Nunes290, Rocio Nuñez-Torres276, Antònia Obrador-Hevia446,447, J. Gonzalo Ocejo-Vinyals33,35, Virginia Olivar376, Silviene F. Oliveira432,433,434,448,449, Lorena Ondo37,275, Alberto Orfao271,272,273,274, Luis Ortega450, Eva Ortega-Paino295, Fernando Ortiz-Flores33,35, Rocio Ortiz-Lopez36,451, José A. Oteo261,402, Harry Pachajoa452,453, Manuel Pacheco392, Fredy Javier Pacheco-Miranda269, Irene Padilla Conejo260, Sonia Panadero-Fajardo327, Mara Parellada255,279,285, Roberto Pariente-Rodríguez378, Estela Paz-Artal407,408,454, Germán Peces-Barba31,455, Miguel S. Pedromingo Kus456, Celia Perales375, Patricia Perez457, César Pérez458, Gustavo Perez-de-Nanclares281,331, Felipe Pérez-García459,460, Patricia Pérez-Matute402, Alexandra Pérez-Serra312,314, M. Elena Pérez-Tomás300, Teresa Perucho461, Lisbeth A. Pichardo260, Susana M. T. Pinho435,462,463, Mel·lina Pinsach-Abuin312,314, Luz Adriana Pinzón287,336, Guillermo Pita276, Francesc Pla-Junca37,464, Laura Planas-Serra37,330, Ericka N. Pompa-Mera465, Gloria L. Porras-Hurtado392, Aurora Pujol37,330,466, María Eugenia Quevedo Chávez268,269, Maria Angeles Quijada280,467, Inés Quintela343, Diana Ramirez-Montaño468, Soraya Ramiro León380, Pedro Rascado Sedes394, Delia Recalde353,354, Emma Recio-Fernández402, Salvador Resino256,313, Adriana P. Ribeiro435,436,463, Carlos S. Rivadeneira-Chamorro287, Diana Roa-Agudelo296, Montserrat Robelo Pardo394, Marilyn Johanna Rodriguez287, Fernando Rodriguez-Artalejo322,351,352,412, Marena Rodríguez-Ferrer269, Carlos Rodriguez-Gallego32,469, José A. Rodriguez-Garcia260, María A. Rodriguez-Hernandez317, Antonio Rodriguez-Nicolas389, Agustí Rodriguez-Palmero330,470, Emilio Rodríguez-Ruiz45,394, Paula A. Rodriguez-Urrego296, Belén Rodríguez Maya250, German Ezequiel Rodriguez Novoa376, Federico Rojo274,471, Andrea Romero-Coronado269, Filomeno Rondón García260, Lidia S. Rosa472, Antonio Rosales-Castillo473, Cladelis Rubio474,475, María Rubio Olivera283,284, Montserrat Ruiz37,330, Francisco Ruiz-Cabello389,414,476, Eva Ruiz-Casares461, Juan J. Ruiz-Cubillan33,35, Javier Ruiz-Hornillos284,477,478, Pablo Ryan479,480,481, Hector D. Salamanca286,287, Lorena Salazar-García324, Giorgina Gabriela Salgueiro Origlia335, Pedro-Luis Sánchez278,362, Clara Sánchez-Pablo362, Olga Sánchez-Pernaute482, Antonio J. Sánchez López483, María Concepción Sánchez Prados267, Javier Sánchez Real260, Jorge Sánchez Redondo250,484, Cristina Sancho-Sainz401, Anna Sangil308, Arnoldo Santos458, Ney P. C. Santos366, Agatha Schlüter37,330, Sonia Segovia464,485,486, Alex Serra-Llovich346, Fernando Sevil Puras257, Marta Sevilla Porras37,38, Miguel A. Sicolo487,488, Vivian N. Silbiger420, Nayara S. Silva349, Fabiola T. C. Silva290, Cristina Silván Fuentes37, Jordi Solé-Violán31,489,490, José Manuel Soria431, Jose V. Sorlí339,340, Renata R. Sousa432, Juan Carlos Souto252, Karla S. C. Souza328, Vanessa S. Souza345, John J. Sprockel287,336, José Javier Suárez-Rama343, David A. Suarez-Zamora296, Xiana Taboada-Fraga439, Eduardo Tamayo384,491, Alvaro Tamayo-Velasco492, Juan Carlos Taracido-Fernandez397, Nathali A. C. Tavares493, Carlos Tellería353,354, Jair Antonio Tenorio Castaño37,38,445, Alejandro Teper376, Juan Torres-Macho494, Lilian Torres-Tobar287, Ronald P. Torres Gutiérrez456, Jesús Troya479, Miguel Urioste441, Juan Valencia-Ramos495, Agustín Valido270,496, Juan Pablo Vargas Gallo497,498, Belén Varón499, Romero H. T. Vasconcelos493, Tomas Vega500, Santiago Velasco-Quirce501, Valentina Vélez-Santamaría329,330, Virginia Víctor283,284, Julia Vidán Estévez260, Miriam Vieitez-Santiago33,35, Carlos Vilches502, Lavinia Villalobos260, Felipe Villar455, Judit Villar-Garcia503,504,505, Cristina Villaverde37,275, Pablo Villoslada-Blanco402, Ana Virseda-Berdices313, Zuleima Yáñez269, Antonio Zapatero-Gaviria506, Ruth Zarate507, Sandra Zazo471, Miguel López de Heredia37, Ingrid Mendes37, Rocío Moreno37, Esther Sande37,44,45, Carlos Flores29,30,31,32, José A. Riancho33,34,35, Augusto Rojas-Martinez36, Pablo Lapunzina37,38,445 & Angel Carracedo37,44,45,46,343 250Hospital Universitario Mostoles, Medicina Interna, Madrid, Spain. 251Universidad Francisco de Vitoria, Madrid, Spain. 252Haemostasis and Thrombosis Unit, Hospital de la Santa Creu i Snt Pau, IIB Sant Pau, Barcelona, Spain. 253Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. 254Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0002), Instituto de Salud Carlos III, Madrid, Spain. 255School of Medicine, Universidad Complutense, Madrid, Spain. 256Centro de Investigación Biomédica en Red de Enfermedades Infecciosas Article (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain. 257Hospital General Santa Bárbara de Soria, Soria, Spain. 258Pediatric Neurology Unit, Department of Pediatrics, Navarra Health Service Hospital, Pamplona, Spain. 259Navarra Health Service, NavarraBioMed Research Group, Pamplona, Spain. 260Complejo Asistencial Universitario de León, León, Spain. 261Infectious Diseases Department, Hospital Universitario San Pedro, Logroño, Spain. 262Fundación Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Hospital de Neurorehabilitació, Barcelona, Spain. 263Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 264Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain. 265Hospital General de Occidente, Guadalajara, Mexico. 266Microbiology Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain. 267Servicio de Neumología, Hospital Universitario La Paz-IDIPAZ, Madrid, Spain. 268Camino Universitario Adelita de Char, Mired IPS, Barranquilla, Colombia. 269Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla, Colombia. 270Neumología, Hospital Universitario Virgen Macarena, Seville, Spain. 271Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain. 272Centro de Investigación del Cáncer (IBMCC), Universidad de Salamanca, CSIC, Salamanca, Spain. 273Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. 274Centre for Biomedical Network Research on Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. 275Department of Genetics & Genomics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital— Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 276Human Genotyping— CEGEN Unit, Spanish National Cancer Research Centre, Madrid, Spain. 277Servicio de Medicina Interna, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. 278Universidad de Salamanca, Salamanca, Spain. 279Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón (IiSGM), Madrid, Spain. 280Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain. 281Biocruces Bizkai HRI, Barakaldo, Spain. 282Cruces University Hospital, Osakidetza, Barakaldo, Spain. 283Hospital Infanta Elena, Madrid, Spain. 284Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 285Centre for Biomedical Network Research on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. 286Fundación Hospital Infantil Universitario de San José, Bogotá, Colombia. 287Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia. 288Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 289Departamento de Medicina Clínica, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 290Departamento de Genética e Morfologia, Instituto de Ciências Biológicas, Universidade de Brasília, Brasilia, Brazil. 291Colégio Marista de Brasilia, Brasilia, Brazil. 292Associação Brasileira de Educação e Cultura, Londrina, Brazil. 293Servicio de Medicina Interna, Hospital Universitario La Paz-IDIPAZ, Madrid, Spain. 294Fundació Docència I Recerca Mutua Terrassa, Barcelona, Spain. 295Spanish National Cancer Research Center, CNIO Biobank, Madrid, Spain. 296Departamento Patologia y Laboratorios, Fundación Santa Fe de Bogota, Bogotá, Colombia. 297Hospital General de Occidente, Zapopan, Mexico. 298Centro Universitario de Tonalá, Universidad de Guadalajara, Tonalá, Mexico. 299Centro de Investigación Multidisciplinario en Salud, Universidad de Guadalajara, Guadalajara, Mexico. 300Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain. 301Universidad Católica San Antonio de Murcia (UCAM), Murcia, Spain. 302Servicio de Medicina Interna-Unidad de Enfermedades Infecciosas, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. 303Department of Internal Medicine, Hospital Universitario de Fuenlabrada, Madrid, Spain. 304Laboratorio de Vigilancia Molecular Aplicada, Escola Tecnica de Saúde, Pará, Brazil. 305Genetics Postgraduate Program, Federal University of Pernambuco, Recife, Brazil. 306Servicio de Alergia, Hospital Universitario Infanta Leonor, Madrid, Spain. 307Servicio de Medicina Intensiva, Hospital Universitario del Tajo, Toledo, Spain. 308Hospital Universitario Mutua Terrassa, Barcelona, Spain. 309Servicio de Farmacología, Hospital Universitario La Paz-IDIPAZ, Madrid, Spain. 310Alcaldía de Barranquilla, Secretaría de Salud, Barranquilla, Colombia. 311Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. 312Centre for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain. 313Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 314Cardiovascular Genetics Center, Institut d’Investigació Biomèdica Girona (IDIBGI), Girona, Spain. 315Medical Science Department, School of Medicine, University of Girona, Girona, Spain. 316Cardiology Service, Hospital Josep Trueta, Girona, Spain. 317Institute of Biomedicine of Seville (IBiS), Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, Virgen del Rocio University Hospital, Seville, Spain. 318Division of Infectious Diseases, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 319Intensive Care Unit, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain. 320Hospital Universitario Mutua Terrassa, Terrassa, Spain. 321Departemento de Medicina, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain. 322Centre for Biomedical Network Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. 323Instituto de Biomedicina de Sevilla, Seville, Spain. 324Facultad de Ciencias, Universidad de los Andes, Bogotá, Colombia. 325Department of Nutrition, University of Fortaleza (UNIFOR), Fortaleza, Brazil. 326Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil. 327Andalusian Public Health System Biobank, Granada, Spain. 328Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 329Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. 330Bellvitge Biomedical Research Institute (IDIBELL), Neurometabolic Diseases Laboratory, L’Hospitalet de Llobregat, Barcelona, Spain. 331Osakidetza, Cruces University Hospital, Barakaldo, Spain. 332Centre for Biomedical Network Research on Diabetes and Metabolic Associated Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. 333University of Pais Vasco, UPV/EHU, Bizkaia, Spain. 334Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-Servizo Galego de Saúde, Vigo, Spain. 335Hospital Universitario La Paz, Hospital Carlos III, Madrid, Spain. 336Hospital de San José, Sociedad de Cirugía de Bogota, Bogotá, Colombia. 337Hospital Universitario Río Hortega, Valladolid, Spain. 338Servicio de Medicina Intensiva, Complejo Hospitalario Universitario de A Coruña (CHUAC), Sistema Galego de Saúde (SERGAS), A Coruña, Spain. 339Preventive Medicine Department, Valencia University, Valencia, Spain. 340Centre for Biomedical Network Research on Physiopatology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 341Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, Magdeburg, Germany. 342Maternidade Escola Janário Cicco, Natal, Brazil. 343Centro Nacional de Genotipado (CEGEN), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. 344Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón (IiSGM), Madrid, Spain. 345Programa de Pós Graduação em Ciências da Saúde, Faculdade de Medicina, Universidade de Brasília, Brasilia, Brazil. 346Fundació Docència I Recerca Mutua Terrassa, Terrassa, Spain. 347Unidad de Genética, Hospital Universitario Mostoles, Madrid, Spain. 348Internal Medicine Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 349Universidade Federal do Rio Grande do Norte, Pós-graduação em Biotecnologia, Rede de Biotecnologia do Nordeste (Renorbio), Natal, Brazil. 350Servicio de Medicina Interna, Hospital Universitario Severo Ochoa, Madrid, Spain. 351Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. 352IdiPaz (Instituto de Investigación Sanitaria Hospital Universitario La Paz), Madrid, Spain. 353Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain. 354Instituto Investigación Sanitaria Aragón (IIS-Aragon), Zaragoza, Spain. 355Programa de Pós Graduação em Nutrição, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 356Preventive Medicine Department, Instituto de Investigacion Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-Servizo Galego de Saúde, Vigo, Spain. 357Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Seville, Spain. 358Departamento de Infectologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 359Hospital de Doenças Infecciosas Giselda Trigueiro, Natal, Brazil. 360Unidad Diagnóstico Molecular, Fundación Rioja Salud, La Rioja, Spain. 361Hospital Universitario Quironsalud Madrid, Madrid, Spain. 362Servicio de Cardiología, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. 363Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro, Majadahonda, Spain. 364Biocruces Bizkaia Health Research Institute, Galdakao University Hospital, Osakidetza, Bizkaia, Spain. 365Instituto Regional de Investigación en Salud- Universidad Nacional de Caaguazú, Caaguazú, Paraguay. 366Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Brazil. 367Departamento de Ensino e Pesquisa, Hospital Ophir Loyola, Belém, Brazil. 368Fundación Asilo San Jose, Santander, Spain. 369Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro, Instituto de Investigación Sanitaria Puerta de Hierro—Segovia de Arana, Madrid, Spain. 370Universidad Nacional de Asunción, Facultad de Politécnica, Paraguay. 371Urgencias Hospitalarias, Complejo Hospitalario Universitario de A Coruña (CHUAC), Sistema Galego de Saúde (SERGAS), A Coruña, Spain. 372Grupo de Investigación en Interacciones Gen-Ambiente y Salud (GIIGAS), Instituto de Biomedicina (IBIOMED), Universidad de León, León, Spain. 373Pediatrics Department, Hospital Universitario Niño Jesús, Madrid, Spain. 374Unitat de Malalties Infeccioses i Importades, Servei de Pediatría, Infectious and Imported Diseases, Pediatric Unit, Hospital Universitari Sant Joan de Deú, Barcelona, Spain. 375Microbiology Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospita, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 376Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina. 377University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. 378Department of Immunology, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain. 379Servicio de Medicina Intensiva, Hospital Infanta Elena, Madrid, Spain. 380Servicio de Genética, Hospital Universitario de Getafe, Madrid, Spain. 381Pneumology Department, Hospital General Universitario Gregorio Marañón (iiSGM), Madrid, Spain. 382Ministerio de Salud Ciudad de Buenos Aires, Buenos Aires, Argentina. 383Unidad de Apoyo a la Investigación, Hospital Clinico Universitario de Valladolid, Valladolid, Spain. 384Departamento de Cirugía, Universidad de Valladolid, Valladolid, Spain. 385Secretaria Municipal de Saude de Apodi, Natal, Brazil. 386Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, Servicio Murciano de Salud, Murcia, Spain. 387Departamento Cirugía, Pediatría, Obstetricia y Ginecología, Facultad de Medicina, Universidad de Murcia (UMU), Murcia, Spain. 388Grupo Clínico Vinculado, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. 389Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain. 390Hospital Universitario Centro Dermatológico Federico Lleras Acosta, Bogotá, Colombia. 391Intermediate Respiratory Care Unit, Department of Pneumology, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 392Clinica Comfamiliar Risaralda, Pereira, Colombia. 393Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara, Mexico. 394Unidad de Cuidados Intensivos, Hospital Clínico Universitario de Santiago (CHUS), Sistema Galego de Saúde (SERGAS), Santiago de Compostela, Spain. 395Plataforma de Farmacogenética, IIS La Fe, Valencia, Spain. 396Departamento de Farmacología, Universidad de Valencia, Valencia, Spain. 397Data Analysis Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 398Infectious Diseases Service, Hospital del Mar, Barcelona, Spain. 399Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain. 400CEXS-Universitat Pompeu Fabra, Spanish Network for Research in Infectious Diseases (REIPI), Barcelona, Spain. 401Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Osakidetza, Bizkaia, Spain. 402Infectious Diseases, Microbiota and Metabolism Unit, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain. 403Sabin Medicina Diagnóstica, São Paulo, Brazil. 404Opthalmology Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 405Pediatric Critical Care Unit, Hospital Sant Joan de Deu, Barcelona, Spain. 406Paediatric Intensive Care Unit, Agrupación Hospitalaria Clínic-Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain. 407Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. 408Transplant Immunology and Immunodeficiencies Group, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. 409SIGEN Alianza Universidad de los Andes, Fundación Santa Fe de Bogotá, Bogotá, Colombia. 410Medicina Intensiva, Hospital General de Segovia, Segovia, Spain. 411Clinical Trials Unit, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 412IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain. 413Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen de las Nieves, Granada, Spain. 414Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. 415Departamento de Medicina, Universidad de Granada, Granada, Spain. 416Servicio de Inmunología, Hospital Universitario La Paz-IDIPAZ, Madrid, Spain. 417Lymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, Spain. 418Intensive Care Unit, Hospital Universitario de Canarias, La Laguna, Spain. 419Dirección General de Salud Pública, Consejería de Sanidad, Junta de Castilla y León, Valladolid, Spain. 420Departamento de Analises Clinicas e Toxicologicas, Universidade Federal do Rio Grande do Norte, Natal, Brazil. 421Epidemiology, Fundación Jiménez Díaz, Madrid, Spain. 422Department of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. 423Instituto de Biomedicina (IBIOMED), Universidad de León, León, Spain. 424Intensive Care Unit, Hospital Universitario N. S. de Candelaria, Santa Cruz de Tenerife, Spain. 425Preventive Medicine Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 426Departamento de Medicina, Universidad de Valladolid, Valladolid, Spain. 427Servicio de Medicina Intensiva, Hospital Universitario Infanta Leonor, Madrid, Spain. 428Servicio de Medicina Interna, Sanatorio Franchin, Buenos Aires, Argentina. 429Unidad de Genética y Genómica Islas Baleares, Hospital Universitario Son Espases, Islas Baleares, Spain. 430Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitario Son Espases, Islas Baleares, Spain. 431Genomics of Complex Diseases Unit, Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain. 432Faculdade de Medicina, Universidade de Brasília, Brasilia, Brazil. 433Programa de Pós-Graduação em Ciências Médicas, Universidade de Brasília, Brasilia, Brazil. 434Programa de Pós-Graduação em Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil. 435Hospital das Forças Armadas, Brasília, Brazil. 436Exército Brasileiro, Cruzeiro, Brazil. 437Hospital El Bierzo, Gerencia de Asistencia Sanitaria del Bierzo (GASBI), Gerencia Regional de Salud (SACYL), Ponferrada, Spain. 438Grupo INVESTEN, Instituto de Salud Carlos III, Madrid, Spain. 439Unidad de Cuidados Intensivos, Complejo Universitario de A Coruña (CHUAC), Sistema Galego de Saúde (SERGAS), A Coruña, Spain. 440Unidad Cuidados Intensivos, Hospital El Bierzo, León, Spain. 441Familial Cancer Clinical Unit, Spanish National Cancer Research Centre, Madrid, Spain. 442Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), Madrid, Spain. 443Departamento de Enfermería, Universidad de Sevilla, Seville, Spain. 444Hospital General Universitario Gregorio Marañón (IiSGM), Madrid, Spain. 445ERN-ITHACA-European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium. 446Unidad de Genética y Genómica Islas Baleares, Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitario Son Espases, Islas Baleares, Spain. 447Instituto de Investigación Sanitaria Islas Baleares (IdISBa), Islas Baleares, Spain. 448Programa de Pós-Graduação em Biologia Animal, Universidade de Brasília, Brasília, Brazil. 449Programa de Pós-Graduação Profissional em Ensino de Biologia, Universidade de Brasília, Brasília, Brazil. 450Anatomía Patológica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos (HCSC), Madrid, Spain. 451Tecnológico de Monterrey, Monterrey, Mexico. 452Centro de Investigación en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia. 453Departamento de Genetica, Fundación Valle del Lili, Cali, Colombia. 454Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid, Madrid, Spain. 455Department of Neumology, Instituto de Investigación Sanitaria– Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 456Hospital Nuestra Señora de Sonsoles, Ávila, Spain. 457Inditex, A Coruña, Spain. 458Intensive Care Department, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 459Servicio de Microbiología Clínica, Hospital Universitario Príncipe de Asturias, Madrid, Spain. 460Departamento de Biomedicina y Biotecnología, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá de Henares, Madrid, Spain. 461GENYCA, Madrid, Spain. 462Marinha do Brasil, Brasil, Brazil. 463Universidade de Brasília, Brasilia, Brazil. 464Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 465Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Instituto Mexicano del Seguro Social (IMSS), Centro Médico Nacional Siglo XXI, Mexico City, Mexico. 466Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. 467Drug Research Centre, Institut d’Investigació Biomèdica Sant Pau, IIB-Sant Pau, Barcelona, Spain. 468Departamento de Genetica, Clinica imbanaco, Cali, Colombia. 469Department of Immunology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain. 470Pediatrics Department, University Hospital Germans Trias i Pujol, Badalona, Spain. 471Department of Pathology, Biobank, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 472Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil. 473Servicio de Medicina Interna, Hospital Universitario Virgen de las Nieves, Granada, Spain. 474Grupo de Ciencias Básicas en Salud (CBS), Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia. 475Sociedad de Cirugía de Bogotá, Hospital de San José, Bogotá, Colombia. 476Departamento Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain. 477Allergy Unit, Hospital Infanta Elena, Madrid, Spain. 478Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain. 479Hospital Universitario Infanta Leonor, Madrid, Spain. 480Complutense University of Madrid, Madrid, Spain. 481Gregorio Marañón Health Research Institute (IiSGM), Madrid, Spain. 482Reumathology Service, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain. 483Biobank, Puerta de Hierro-Segovia de Arana Health Research Institute, Madrid, Spain. 484Universidad Rey Juan Carlos, Madrid, Spain. 485The John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 486Neuromuscular Unit, Neuropediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain. 487Casa de Saúde São Lucas, Natal, Brazil. 488Hospital Rio Grande, Natal, Brazil. 489Intensive Care Unit, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria, Spain. 490Universidad Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. 491Servicio de Anestesiologia y Reanimación, Hospital Clinico Universitario de Valladolid, Valladolid, Spain. 492Servicio de Hematologia y Hemoterapia, Hospital Clinico Universitario de Valladolid, Valladolid, Spain. 493Hospital Universitario Lauro Wanderley, João Pessoa, Brazil. 494Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain. 495University Hospital of Burgos, Burgos, Spain. 496Universidad de Sevilla, Seville, Spain. 497Fundación Santa Fe de Bogota, Instituto de Servicios Medicos de Emergencia y Trauma, Bogotá, Colombia. 498Universidad de los Andes, Bogotá, Colombia. 499Quironprevención, A Coruña, Spain. 500Junta de Castilla y León, Consejería de Sanidad, Valladolid, Spain. 501Gerencia Atención Primaria de Burgos, Burgos, Spain. 502Immunogenetics–Histocompatibility group, Servicio de Inmunología, Instituto de Investigación Sanitaria Puerta de Hierro, Segovia de Arana, Madrid, Spain. 503Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain. 504IMIM—Hospital del Mar Medical Research Institute, Institut Hospital del Mar d’Investigacions Mediques, Barcelona, Spain. 505Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 506Consejería de Sanidad, Comunidad de Madrid, Madrid, Spain. 507Centro para el Desarrollo de la Investigación Científica, Asunción, Paraguay. ISARICC Investigators Co-Investigators J. Kenneth Baillie1,2,3,11, Peter J. M. Openshaw12,26, Malcolm G. Semple16,17, Beatrice Alex508, Petros Andrikopoulos509,510, Benjamin Bach508, Wendy S. Barclay511, Debby Bogaert18, Meera Chand512, Kanta Chechi509,513, Graham S. Cooke514, Ana da Silva Filipe515, Thushan de Silva516, Annemarie B. Docherty11,517, Gonçalo dos Santos Correia518,519, Marc-Emmanuel Dumas509,510,520,521, Jake Dunning12,522, Tom Fletcher523, Christopher A. Green524, William Greenhalf525, Julian Griffin509, Rishi K. Gupta526, Ewen M. Harrison517, Antonia Y. W. Ho515,527, Karl Holden528, Peter W. Horby21, Samreen Ijaz529, Say Khoo530, Paul Klenerman531,532, Andrew Law3, Matthew Lewis518,519, Sonia Liggi509, Wei Shen Lim533, Lynn Maslen518,519, Alexander J. Mentzer534,535, Laura Merson536, Alison M. Meynert2, Shona C. Moore537, Mahdad Noursadeghi538, Michael Olanipekun509,510, Anthonia Osagie509,510, Massimo Palmarini515, Carlo Palmieri539,540, William A. Paxton537,541, Georgios Pollakis537,541, Nicholas Price542,543, Andrew Rambaut544, David L. Robertson515, Clark D. Russell18, Vanessa Sancho-Shimizu545, Caroline Sands518,519, Janet T. Scott515,546, Louise Sigfrid536, Tom Solomon16,547, Shiranee Sriskandan514,548, David Stuart8, Charlotte Summers19, Olivia V. Swann549, Zoltan Takats509,550, Panteleimon Takis518,519, Richard S. Tedder551,552,553, A. A. Roger Thompson554, Emma C. Thomson515, Ryan S. Thwaites12, Lance C. W. Turtle16,555, Maria Zambon522 & Gail Carson536 Data Analysis Team Thomas M. Drake517, Cameron J. Fairfield517, Stephen R. Knight517, Kenneth A. Mclean517, Derek Murphy517, Lisa Norman517, Riinu Pius517 & Catherine A. Shaw517 Data Architecture Team Marie Connor556, Jo Dalton556, Carrol Gamble556, Michelle Girvan556, Sophie Halpin556, Janet Harrison556, Clare Jackson556, Laura Marsh556, Stephanie Roberts556, Egle Saviciute556, Sara Clohisey3, Ross Hendry3, Susan Knight557, Eva Lahnsteiner557, Andrew Law3, Gary Leeming558, Lucy Norris559, James Scott-Brown508, Sarah Tait557 & Murray Wham2 Data Analysis and Management Team James Lee560, Daniel Plotkin560 & Seán Keating11 Project Administration Team Cara Donegan561 & Rebecca G. Spencer561 Project Management Team Chloe Donohue556, Fiona Griffiths3, Hayley Hardwick16 & Wilna Oosthuyzen3 508School of Informatics, University of Edinburgh, Edinburgh, UK. 509Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Sir Alexander Fleming Building, Imperial College London, London, UK. 510Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, London, UK. 511Section of Molecular Virology, Imperial College London, London, UK. 512Antimicrobial Resistance and Hospital Acquired Infection Department, Public Health England, London, UK. 513Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK. 514Department of Infectious Disease, Imperial College London, London, UK. 515MRC-University of Glasgow Centre for Virus Research, Glasgow, UK. 516The Florey Institute for Host-Pathogen Interactions, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. 517Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK. 518National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. 519Section of Bioanalytical Chemistry, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. 520European Genomic Institute for Diabetes, CNRS UMR 8199, INSERM UMR 1283, Institut Pasteur de Lille, Lille University Hospital, University of Lille, Lille, France. 521McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada. 522National Infection Service, Public Health England, London, UK. 523Liverpool School of Tropical Medicine, Liverpool, UK. 524Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK. 525Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. 526Institute for Global Health, University College London, London, UK. 527Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK. 528University of Liverpool, Liverpool, UK. 529Virology Reference Department, National Infection Service, Public Health England, London, UK. 530Department of Pharmacology, University of Liverpool, Liverpool, UK. 531Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK. 532Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 533Nottingham University Hospitals NHS Trust, Nottingham, UK. 534Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK. 535Department of Microbiology/Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. 536ISARIC Global Support Centre, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 537Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK. 538Division of Infection and Immunity, University College London, London, UK. 539Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Article Biology, University of Liverpool, Liverpool, UK. 540Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK. 541NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK. 542Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London, London, UK. 543Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. 544Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK. 545Department of Pediatrics and Virology, St Mary’s Medical School Building, Imperial College London, London, UK. 546NHS Greater Glasgow & Clyde, Glasgow, UK. 547Walton Centre NHS Foundation Trust, Liverpool, UK. 548MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK. 549Department of Child Life and Health, University of Edinburgh, Edinburgh, UK. 550National Phenome Centre, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. 551Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK. 552Transfusion Microbiology, National Health Service Blood and Transplant, London, UK. 553Department of Medicine, Imperial College London, London, UK. 554Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. 555Tropical & Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, UK. 556Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK. 557Public Health Scotland, Edinburgh, UK. 558Centre 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. 559EPCC, University of Edinburgh, Edinburgh, UK. 560ISARIC, Global Support Centre, COVID-19 Clinical Research Resources, Epidemic diseases Research Group, Oxford (ERGO), University of Oxford, Oxford, UK. 561Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK. The 23andMe COVID-19 Team Janie F. Shelton562, Anjali J. Shastri562, Chelsea Ye562, Catherine H. Weldon562, Teresa Filshtein-Sonmez562, Daniella Coker562, Antony Symons562, Jorge Esparza-Gordillo563, Stella Aslibekyan562 & Adam Auton562 56223andMe, Sunnyvale, CA, USA. 563Human genetics R&D, GSK Medicines Research Centre, Target Sciences R&D, Stevenage, UK. Methods Hospitalization meta-analysis The hospitalized phenotype includes patients who were hospitalized with a laboratory-confirmed SARS-Cov2 infection. In this analysis we included GenOMICC, GenOMICC Brazil, GenOMICC Saudi Arabia, ISARIC4C, HGIv6 B2 phenotype with subtraction of GenOMICC data, SCOURGE hospitalized versus population and mild cases, and 23andMe broad respiratory phenotype. A summary description of each analy- sis is given above, a table with the included studies can be found in Supplementary Table 14 and an extended description can be found in Supplementary Table 1. Critical illness meta-analysis The critically ill COVID-19 group included patients who were hospi- talized owing to symptoms associated with laboratory-confirmed SARS-CoV-2 infection and who required respiratory support or whose cause of death was associated with COVID-19. In the critical illness analy- sis, we included GenOMICC, patients with critical illness from ISARIC4C, HGIv6 phenotype A2 with subtraction of GenOMICC data, SCOURGE severity grades 3 and 4 versus population controls, and 23andMe res- piratory support phenotype. A summary description of each analysis can be found above, a table with the included studies can be found in Supplementary Table 13 and an extended description can be found in Supplementary Table 1. Meta-analyses All meta-analyses across studies were performed using a fixed-effect inverse-variance weighting method and control for population stratifi- cation in the METAL software23. Allele frequency was calculated as the average frequency across studies with the METAL option AVERAGE- FREQ. P values for heterogeneity in effect sizes between studies were calculated using a Cochran’s Q-test implemented in METAL. For variants in the same position with different REF and ALT alleles across studies, the GenoMICC variant in the European population was selected and the rest were removed. Finally, variants with switched ALT and REF alleles between HGIv6 and GenOMICC were also removed on the basis of dif- ferences in allele frequency of the alternative allele. Variants were anno- tated to the closest genes using dbsnp v.b151 GRCh38p7 and bionrRt R package (v.2.46.3)24. As each single-nucleotide polymorphism (SNP) of the meta-analysis can be present in different subsets of cohorts, there may be large differences in P values in SNPs with a high level of linkage disequilibrium, which may have an effect on downstream analyses. For this reason, variants that were not present in one of the three biggest studies—GenOMICC European ancestry, HGIv6 or SCOURGE—were filtered out from post-GWAS analysis. Conditional analysis We performed a step-wise conditional analysis to find independent signals. As European-specific data are not available in some cohorts but European ancestry is largely predominant (87.2% of cases with criti- cal illness), we performed the conditional analysis using a European reference panel and the meta-analysis results of the whole cohort. To perform the conditional analysis, we used the GCTA (v.1.9.3) --cojo-slct function25. The parameters for the function were P = 5 × 10−8, a distance of 10,000 kb and a co-linear threshold of 0.9 (ref. 26), and the reference population for the conditional analysis was individuals of European ancestry with whole-genome sequence available in the GenOMICC study and whole genomes from the 100,000 Genomics England project2. Credible set fine-mapping We performed fine-mapping using the SuSiE model27 to construct credible sets for the independent signals identified using conditional analysis. As for conditional analysis, we used a European reference panel and the meta-analysis results of the whole critical illness cohort. We performed analyses in 1 Mb windows centred on the lead variants identified through conditional analysis. In cases in which windows for multiple variants overlapped, they were joined into a single window. For each window, we fitted the SuSiE summary statistics model set- ting the expected number of independent signals to the number of identified though conditional analysis. Models for three windows did not converge in 500 iterations and have been excluded. As a reference, we used the publically available linkage disequilibrium information for non-Finish Europeans from the GNOMAD 2.1.1 release. Full data for all variants included in credible sets are included in Supplementary Table 5. Gene-level analysis We performed an analysis summarizing the genetic associations at the gene level using the mBAT-combo method28. We used the COVID ‘all critical cohorts’ meta-analysis (GenOMICC, HGIv6 phenotype A2, SCOURGE and 23andMe) summary statistics. As this is a trans-ethnic meta-analysis, we used a mixed ancestry linkage disequilibrium refer- ence panel, consisting of 3,202 1000 Genomes phase 3 samples. We considered a list of protein-coding genes with unique ensemble gene ID based on the release from GENCODE (v.40) for hg38, which can be found on the mBAT-combo website (https://yanglab.westlake.edu.cn/ software/gcta/#mBAT-combo). A gene region was taken to span 50 kb upstream to 50 kb downstream of the gene’s untranslated regions. Sex-stratified meta-analysis To test for differences in genetic effects, we performed sex-stratified GWAS of the COVID-19 critical illness phenotype in the European ances- try GenOMICC WGS and genotyped cohorts and SCOURGE. We then performed a meta-analysis for each sex following the same methods as for the main analysis. We tested for differences in effects between the meta-analyses of the two sexes following previously described methods29. Mendelian randomization GSMR5 was performed. We used the COVID ‘all critical cohorts’ meta-analysis (GenOMICC, HGIv6 phenotype A2, SCOURGE and 23andMe) as the outcome, protein expression quantitative-trait loci (pQTLs) from ref. 30 and RNA expression quantitative-trait loci (eQTLs) from eQTLgen31 (2019-12-23 data release) as exposures, and 10,000 indi- viduals of European ancestry randomly sampled from the UK Biobank as the linkage disequilibrium reference cohort (50,000 for linkage disequilibrium to missense variant plots). GSMR was performed for all exposures for which we were able to identify two or more suitable SNPs. SNPs were chosen to meet the following criteria: (1) SNP to exposure association P < 5 × 10−8; (2) linkage disequilibrium clumping lead SNPs only (±1 Mb, r2 < 0.05); (3) SNP not removed by HEIDI-outlier filtering (for the removal of SNPs with evidence of horizontal pleiotropy) at the default threshold value of 0.01. eQTLGen effect sizes and stand- ard errors were estimated as described in supplementary note 2 of ref. 32. We considered as significant those exposure–outcome pairs with FDR < 0.05. TWAS analysis To perform TWAS analysis in GTExv8 tissues33, we used the MetaXcan framework and the GTExv8 eQTL and sQTL MASHR-M models avail- able for download online (http://predictdb.org/) and the ‘all critical cohorts’ meta-analysis. We first calculated individual TWAS for whole blood and lungs using the S-PrediXcan function34,35. We next performed a metaTWAS including data from all tissues to increase the statistical power using s-MultiXcan36. We applied Bonferroni correction to the results to choose significant genes and introns for each analysis. Monocyte gene expression To detect eQTLs, untreated primary monocytes were prepared from 174 healthy individuals of Northern European (British) ancestry recruited https://yanglab.westlake.edu.cn/software/gcta/#mBAT-combo https://yanglab.westlake.edu.cn/software/gcta/#mBAT-combo http://predictdb.org/ Article through the Oxford Biobank. Poly(A) RNA was paired-end 100 bp sequenced in the Oxford Genome Centre using the Illumina HiSeq- 4000 machines (median = 47,735,438 reads per sample). Reads were aligned to CRGh38/hg38 using HISAT2 with the default parameters. High mapping quality reads were selected on the basis of MAPQ score using bamtools. Duplicate reads were marked and removed using pic- ard (v.1.105). Samtools was used to pass through the mapped reads and calculate statistics. Read count information was generated using HTSeq and normalized using DESeq2. Sample contamination and swaps were detected by comparing the imputed SNP-array genotypes with genotypes called from RNA-seq using verifyBamID. Genotyping was performed with Illumina HumanOmniExpress with coverage of 733,202 separate markers. Genotypes were pre-phased with SHAPEIT2, and missing genotypes were imputed with PBWT. Poly(A) RNA was paired-end sequenced at the Oxford Genome Centre using the Illumina HiSeq-4000 machines. vcftools (v0.1.12b) was applied on genetic varia- tion data in the form of variant call format (VCF) files to filter out indels and SNPs with a minor allele frequency of less than 0.04. TWAS analysis for monocyte data was performed using genotyp- ing and monocyte RNA-sequencing data from 174 individuals. Using a region of 500 kb around each gene, we calculated gene expression models using the Fusion R package37. For each gene, three models were calculated adding as covariates the two first principal components calculated from the genotype: blup, elastic networks and lasso. The model with a better r2 between predicted and measured expression in a fivefold cross-validation was chosen. Then SNP genetic heritability was calculated for the 500 kb region for each gene and those genes with a nominal significant SNP heritability estimate (P ≤ 0.01) were chosen for the TWAS analysis. Summary statistics for the ‘all critical cohorts’ meta-analysis and the best model for each gene were then used to perform the TWAS. Colocalization Significant genes in the TWAS and metaTWAS were selected for a colo- calization analysis using the coloc R package. The lead SNPs and a region of 200 Mb around the gene were used to colocalize with significant genes in the TWAS with eQTL summary statistics data on the region from GTExv8 lung, GTExv8 whole blood, eQTLgen or monocyte eqtl. As in our previous analysis2, we first performed a sensitivity analysis of the posterior probability of colocalization (PPH4) on the prior probability of colocalization (P12), going from P12 = 10−8 to P12 = 10−4, with the default threshold being P12 = 10−5. eQTL signal and GWAS signals were deemed to colocalize if these two criteria were met: (1) at P12 = 5 × 10−5 the probability of colocalization PPH4 > 0.5; and (2) at P12 = 10−5 the probability of independent signal (PPH3) was not the main hypothesis (PPH3 < 0.5). These criteria were chosen to allow eQTLs with weaker P values, owing to lack of power in GTEx v.8, to be colocalized with the signal when the main hypothesis using small priors was that there was not any signal in the eQTL data. Effect comparison We compared the estimates of effect sizes between the individual GWASs used in the meta-analysis, for all variants that were genome-wide significant in at least one of the individual GWASs. To this end, we regressed the effects obtained using critical illness and hospitali- zation in the SCOURGE and 23andMe cohorts, as well as the HGI meta-analyses on the effect estimates obtained using the GenOMICC cohort. To account for estimation errors present in both the depend- ent and independent variables of the regression we used orthogonal distance regression38. Weight of studies To calculate the weight of GenOMICC, we downloaded the leave-one-out data of HGIv7. As the meta-analysis is performed using a variance- weighted method, we can recover the variance for each SNP as v = 1 s.e.2 , for the meta-analysis of all of the cohorts and for each one of the leave- one-out analysis. The total weight is w = vtot 1 and the weight leaving out a specific study is w = vloo 1 loo . The weight of a cohort is then w w−tot loo. We calculated the weight for each the significant SNPs in our analysis for each study and normalized it using the total weight. Finally, we calculated the mean and s.d. from the significant SNPs for each cohort. Forest plots To compare effects between cohorts, we first performed a trans-ancestry meta-analysis for GenOMICC and 23andMe using METAL23. Then, we used the metagen and forest functions of the meta R package to produce forest plots for critical illness and hospitalization separately. Reporting summary Further information on research design is available in the Nature Port- folio Reporting Summary linked to this article. Data availability Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery data- set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/ dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data ser- vice. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111. Code availability Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/bail- lielab/GenOMICC_GWAS). 23. Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). 24. Durinck, S., Spellman, P. T., Birney, E. & Huber, W. Mapping identifiers for the integration of genomic datasets with the r/bioconductor package biomaRt. Nat. Protoc. 4, 1184–1191 (2009). 25. Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011). 26. Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012). 27. Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. B 82, 1273–1300 (2020). 28. Li, A. et al. mBAT-combo: a more powerful test to detect gene-trait associations from GWAS data. Preprint at bioRxiv https://doi.org/10.1101/2022.06.27.497850 (2022). 29. Bernabeu, E. et al. Sex differences in genetic architecture in the UK Biobank. Nature 53, 1283–1289 (2021). 30. Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73–79 (2018). 31. Võsa, U. et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet. 53, 1300–1310 (2021). https://genomicc.org/data https://research.23andMe.com/dataset-access/ https://research.23andMe.com/dataset-access/ https://odap.ac.uk https://doi.org/10.5287/ora-ko7q2nq66 https://ega-archive.org/studies/EGAS00001007111 https://github.com/baillielab/GenOMICC_GWAS https://github.com/baillielab/GenOMICC_GWAS https://doi.org/10.1101/2022.06.27.497850 32. Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016). 33. The GTEX Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020). 34. Gamazon, E. R. et al. A gene-based association method for mapping traits using reference transcriptome data. Nat. Genet. 47, 1091–1098 (2015). 35. Barbeira, A. N. et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun. 9, 1825 (2018). 36. Barbeira, A. N. et al. Integrating predicted transcriptome from multiple tissues improves association detection. PLoS Genet. 15, e1007889 (2019). 37. Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016). 38. Boggs, P. T. & Rogers, J. E. Orthogonal distance regression. Contemp. Math. 112, 183–194 (1990). 39. Liang, J. et al. Lead identification of novel and selective TYK2 inhibitors. Eur. J. Med. Chem. 67, 175–87 (2013). 40. Li, Z. et al. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J. Immunol. 190, 2335–2344 (2013). Acknowledgements We thank the patients and their loved ones who volunteered to contribute to this study at one of the most difficult times in their lives, and the research staff in every intensive care unit who recruited patients at personal risk during the most extreme conditions ever witnessed in most hospitals. GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0). We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg. org/acknowledgements). Author contributions E.P.-C., K. Rawlik, K.M., S.K., C.P.P., J.F.W., V.V., M.A., A.D.L., E.J.P., R.C., A.C., A.F., L.M., K. Rowan, A.C.P., A.L., S.C.H. and J.K.B. contributed to design. E.P.-C., K. Rawlik, A.D.B., T.Q., Y.W., I.N., G.A.M., M.Z., L.K., A.K., A.R., T.M., J.Y., A.L., B.F., S.C.H. and J.K.B. contributed to data analysis. E.P.-C., K. Rawlik, I.N., A.K., A.R., J.M., C.D.R., A.L., B.F. and S.C.H. contributed to bioinformatics. E.P.-C., K. Rawlik, I.N., G.A.M., M.Z., A.K., J.M., C.D.R., R.T., D. McAuley, A.N., M.G.S., B.F., S.C.H. and J.K.B. contributed to writing and reviewing the manuscript. I.N., F.G., W.O., K.M., S.K., D. Maslove, A.N., M.G.S., J.K., M.S.-H., C.S., C.H., P.H., L.L., D. McAuley, H.M., P.J.M.O., C.B., T.W., A.T., C.F., J.A.R., A.R.-M., P.L., C.P.P., A.F., L.M., K. Rowan, A.L., B.F. and S.C.H. contributed to oversight. F.G. and W.O. contributed to project management. F.G., W.O. and J.K.B. contributed to ethics and governance. K.M., A.F. and L.M. contributed to sample handling and sequencing. C.P.P., K. Rowan, S.C.H. and J.K.B. contributed to conception. C.P.P., J.F.W., V.V., M.A., A.D.L., E.J.P., R.C., A.C., K. Rowan and A.C.P. contributed to reviewing the manuscript. K. Rowan and A.L. contributed to clinical data management. J.K.B. contributed to scientific leadership. Competing interests The authors declare no competing interests. Additional information Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41586-023-06034-3. Correspondence and requests for materials should be addressed to J. Kenneth Baillie. Peer review information Nature thanks Jacques Fellay and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Reprints and permissions information is available at http://www.nature.com/reprints. https://www.covid19hg.org/acknowledgements https://www.covid19hg.org/acknowledgements https://doi.org/10.1038/s41586-023-06034-3 http://www.nature.com/reprints Article Extended Data Fig. 1 | Pipeline of meta-analysis and post-GWAS analyses. Red border indicates that the data is only available for the hospitalized phenotype, while a black border indicates that the analysis was performed for the critical illness phenotype. Extended Data Fig. 2 | Miami plots. Meta-analysis results are shown for a) critical and b) hospitalized phenotypes. In each plot results obtained using all cohorts are shown at the top and using GenOMICC data only at the bottom. Independent lead variants in the analyses of all cohorts are annotated with associated genes. Genome-wide significant associations that have not been previously reported are indicated in bold. Article Extended Data Fig. 3 | Comparison of effect size estimates. GenOMICC is compared with the critical and hospitalized phenotype definitions in the SCOURGE, 23andMe, and HGI analyses. The black line indicates the best linear fit, given by the equation in each plot, obtained using Orthogonal Distance Regression to account for estimation errors in both sets of effects in the comparison. Extended Data Fig. 4 | Study weightings for (a) critical and (b) hospitalized COVID-19. Mean +/− standard deviation of weights assigned to each data source in meta-analyses for all significant SNPs. Article Extended Data Fig. 5 | Cartoon showing postulated roles for genes and mediators implicated in the pathogenesis of critical COVID-19 by GenOMICC GWAS, TWAS and Mendelian randomization. Postulated roles for genetic variants are shown in a highly simplified format to illustrate potential roles in pathogenesis, with the shaded background indicating the hypothetical impact of the host immune response over time17. Host immune processes are divided into those that are thought to play a role in controlling viral replication early in disease (orange section, showing “adaptive” response), and those implicated in driving hypoxaemic respiratory failure later in disease (green section, showing “maladaptive” response). Bold type gene names indicate a higher level of confidence in both the gene identification and the biological role. Extended Data Fig. 6 | Functional genomics analyses for TYK2. (a) Effect size plot for effect of multiple variants on TYK2 expression (eQTLgen, x-axis) against increasing susceptibility to critical COVID-19 (βxy = 0.53; P = 1.2 × 10xy −23). Colour shows linkage disequilibrium (LD) with the missense variant rs34536443. (b) Crystal structure of TYK2 kinase domain (Protein Data Bank ID 4GVJ39) in two views that differ by a 45° rotation around a horizontal axis. The side chain of P1104 is shown as connected spheres with a nitrogen atom coloured in blue. Carbon, oxygen, nitrogen and phosphorus atoms of ATP are shown as magenta, red, blue and orange connected spheres, respectively. The N-terminal region of the kinase domain is not shown in the second view for clarity. The right-most panel shows a close view of P1104 and neighbouring residues with their side chains shown as sticks. Numbering of residues corresponds to UniProtKB entry P29597. P1104 is in the catalytic kinase domain and proximal to the ATP-binding site; TYK2 P1104A is catalytically impaired40. https://www.uniprot.org/uniprot/P29597 Article Extended Data Fig. 7 | Steroid treatment and vaccination status. Data are shown for a subset of GenOMICC cases who were also recruited to the ISARIC4C study in the UK. Extended Data Table 1 | pQTL GSMR results table Proteins significantly linked to COVID-19 severity (false discovery rate (FDR) <0.05). Exposure: protein name; b: effect-size estimate of the protein on COVID-19 severity from GSMR; se: standard-error of b; p: p-value of the GSMR result; N: Number of independent SNPs included in the analysis. †: indicates proteins with GSMR evidence previously presented in Kousathanas et al.2. Article Extended Data Table 2 | Replication table Each report of genome-wide significant associations with severe COVID-19 is shown, with associations that were first reported by the GenOMICC consortium are highlighted in blue. 1 nature portfolio | reporting sum m ary M arch 2021 Corresponding author(s): J. Kenneth Baillie Last updated by author(s): Feb 22, 2023 Reporting Summary Nature Portfolio wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Portfolio policies, see our Editorial Policies and the Editorial Policy Checklist. Statistics For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section. n/a Confirmed The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement A statement on whether measurements were taken from distinct samples or whether the same sample was measured repeatedly The statistical test(s) used AND whether they are one- or two-sided Only common tests should be described solely by name; describe more complex techniques in the Methods section. A description of all covariates tested A description of any assumptions or corrections, such as tests of normality and adjustment for multiple comparisons A full description of the statistical parameters including central tendency (e.g. means) or other basic estimates (e.g. regression coefficient) AND variation (e.g. standard deviation) or associated estimates of uncertainty (e.g. confidence intervals) For null hypothesis testing, the test statistic (e.g. F, t, r) with confidence intervals, effect sizes, degrees of freedom and P value noted Give P values as exact values whenever suitable. For Bayesian analysis, information on the choice of priors and Markov chain Monte Carlo settings For hierarchical and complex designs, identification of the appropriate level for tests and full reporting of outcomes Estimates of effect sizes (e.g. Cohen's d, Pearson's r), indicating how they were calculated Our web collection on statistics for biologists contains articles on many of the points above. Software and code Policy information about availability of computer code Data collection Illumina i-scan platform, GenomeStudio Analysis software v2.0.3, GSAMD-24v3-0-EA_20034606_A1.bpm manifest and cluster file provided by manufacturer for GenOMICC UK genotyping. Affymetrix Saub1 chip (Saudi Arabia) and Axiom Analysis suite 5.1.1.1 manifest and cluster file provided by manufacturer for GenOMICC Saudi Arabia. Other datasets were collected previously and Summary statistics used. In order to detect eQTLs, untreated primary monocytes were prepared from 174 healthy individuals of Northern European (British) ancestry recruited via the Oxford biobank. Poly-A RNA was paired-end 100bp sequenced in the Oxford Genome Centre using Illumina Hiseq-4000 machines (median = 47,735,438 reads per sample). Genotyping was performed with Illumina HumanOmniExpress with coverage of 733,202 separate markers. Data analysis GenomeStudio v2.03, Plink 1.9, Plink 2.0, King 2.1, R v3.6.3, python v3.7, GATK 4.0, USC liftover, GCTA v1.92 ,REGENIE v3.1.2, metal (2018-08-28), BCFtools 1.9, QCtools 1.3, FlashPCA2, admixture,1.3.0 SMR/HEIDI v1.03, MetaXcan v0.6.5, MiniMac4 v1.0, MetaSubtract package v1.60, Rv4.1.0, FUSION (commit e1ba5f7), python v3.10, HISAT2, bamtools, picard v.1.105, verifyBAMID, samtools, SHAPEIT2, PBWT, vcftools v.0.1.12b, HTseq, Deseq2. For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Portfolio guidelines for submitting code & software for further information. 2 nature portfolio | reporting sum m ary M arch 2021 Data Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: - Accession codes, unique identifiers, or web links for publicly available datasets - A description of any restrictions on data availability - For clinical datasets or third party data, please ensure that the statement adheres to our policy Downloadable summary data are available through the GenOMICC data site https://genomicc.org/data. Summary statistics will be available without including 23andme summary statistics, except for the 10,000 most significant hits which will have full summary statistics available. The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit https://research.23andMe.com/dataset-access/ for more information and to apply to access the data. All individual-level genotype and whole genome sequence data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform https://odap.ac.uk. A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data is available under the title “Monocyte gene expression data” within the Oxford University Research Archives. DOI: 10.5287/ora-ko7q2nq66 (http://dx.doi.org/10.5287/ora-ko7q2nq66) Human research participants Policy information about studies involving human research participants and Sex and Gender in Research. Reporting on sex and gender Sex was asked in the study, and then confirmed by genotype. When there was a discordance between self-reported sex and genotyped sex the sample was removed from the study. Sex-specific analysis were performed for both males and females but did not give any significant results Overall the study included 45472 cases from which ~40% are female. As data comes from summary statistics from other analysis, it has not been possible to calculate the exact number of females and males. Population characteristics Cases have tested positive for Covid-19 and needed hospitalisation or ICU admission. Controls come from different sources, people which experienced mild (non-hospitalised) Covid-19 or population controls from different Biobanks. In GenOMICC Brazil, mild cases were selected from serological studies of SARS-COV2 infection and PCR test results among health professionals and the general population. In GenOMICC Saudi Arabia, mild controls were selected after a positive PCR test. SCOURGE population controls were extracted from Spanish DNA Biobank and the GR@CE consortium. Participants in 23and me analysis provided informed consent and answered surveys online according to 23andme human subjects research protocol. Untreated primary monocytes were prepared from 174 healthy individuals from British ancestry via the Oxford Biobank Recruitment Cases were recruited by different studies in hospitals. All participants gave informed consent. Mild controls were recruited on the basis of having experienced mild or assymptomatic Covid-19. For GenOMICC UK and ISARIC4C population controls were used from UK Biobank (project 788), or 100,000 genomes from genomics england. SCOURGE project used controls from Spanish DNA Biobank and the GR@CE consortium Ethics oversight GenOMICC Scotland: Scotland A Research Ethics Committee 15/SS/0110. GenOMICC England/Wales/Northern Ireland Coventry and Warwickshire Research Ethics Committtee 19/WM/0247. GenOMICC Brazil (BraCovid) National Research Ethics Committee (CONEP) and Ethics Committee for the Analysis of Research Projects at HC FMUSP (CAPPesq) 5025/20/054. GenOMICC Saudi Arabia IRB at King Abdullah International Medical Research Center. ISARIC4C England/Wales/Northern Ireland South Central Oxford C Research Ethics Committee 13/SC/0149. ISARIC4C Scotland Scotland A Research Ethics Committee 20/SS/0028. SCOURGE Galician Ethical Committee 2020/197. 23andme Ethical and Independent Review Services \url{http://www.eandireview.com}. Covid-19 HGI Multiple ethics committees (https://www.covid19hg.org/). Oxford biobank approved by South Central - Oxford C Research Ethics Committee, reference 18/SC/0588 Note that full information on the approval of the study protocol must also be provided in the manuscript. Field-specific reporting Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection. Life sciences Behavioural & social sciences Ecological, evolutionary & environmental sciences For a reference copy of the document with all sections, see nature.com/documents/nr-reporting-summary-flat.pdf 3 nature portfolio | reporting sum m ary M arch 2021 Life sciences study design All studies must disclose on these points even when the disclosure is negative. Sample size cases 45472, controls 2929541 Data exclusions no exclusions Replication As we meta-analysed all public data available for Covid-19, to verify replicability of the findings we performed a heterogeneity test between studies, using a Cochran's Q-test Randomization Not relevant to the study Blinding Not relevant to the study Reporting for specific materials, systems and methods We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. Materials & experimental systems n/a Involved in the study Antibodies Eukaryotic cell lines Palaeontology and archaeology Animals and other organisms Clinical data Dual use research of concern Methods n/a Involved in the study ChIP-seq Flow cytometry MRI-based neuroimaging GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19 Therapeutic implications Host–pathogen interaction Online content Fig. 1 Functional genomics analyses for SLC22A31 and SFTPD. Fig. 2 GSMR effect sizes. Extended Data Fig. 1 Pipeline of meta-analysis and post-GWAS analyses. Extended Data Fig. 2 Miami plots. Extended Data Fig. 3 Comparison of effect size estimates. Extended Data Fig. 4 Study weightings for (a) critical and (b) hospitalized COVID-19. Extended Data Fig. 5 Cartoon showing postulated roles for genes and mediators implicated in the pathogenesis of critical COVID-19 by GenOMICC GWAS, TWAS and Mendelian randomization. Extended Data Fig. 6 Functional genomics analyses for TYK2. Extended Data Fig. 7 Steroid treatment and vaccination status. Table 1 Genome-wide significant associations with critical COVID-19, listing independent lead variants. Extended Data Table 1 pQTL GSMR results table. Extended Data Table 2 Replication table.