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).

1 The mechanism of observed temporal variations in plasma theophylline concentrations has been investigated.2 Eight healthy volunteers were given both oral and intravenous doses of theophylline (5 mg/kg) at 09.00 h and 21.00 h under controlled conditions. Regular plasma concentration measurements were made following each dose in order to determine the diurnal and nocturnal disposition of the drug.3 Plasma theophylline concentrations at 0.5 h following each oral dose were 6.9 + 0.8 ,ug/iml, a.m., and 3.9 + 0.6 Aglml, p.m. (P < 0.05). Time to peak concentration was 1.69 + 0.28 h, a.m.; 2.13 + 0.23 h, p.m. (P < 0.05). Values for ka were not significantly different, however. Overall bioavailability, volume of distribution and systeimic clearances, calculated for the 12 h period after each dose, did not differ significantly between day and night. 4 Diurnal variations in theophylline disposition do not appear to be the result of changes in metabolism or excretion, but may reflect minor differences in absorption.

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Circadian variation in plasma theophylline concentrations was studied in eight patients with obstructive airways disease during regular 12‐ hourly dosing at 09.00 and 21.00 h with a sustained‐release theophylline formulation. After regular dosing for a minimum period of 3 days, plasma concentration measurements were made at 09.00, 13.00, 21.00 and 01.00 h on 3 consecutive days and at more regular intervals during a complete 24 h period on day 4. On each day, theophylline concentrations for the first 4 h of the dosing interval were consistently higher during the day than at night. However, the differences were significant only at 13.00/01.00 h on day 2, and for each of the first 4 h on day 4. On day 4, following the dose at 21.00 h the mean peak plasma theophylline concentration occurred 6.9 +/‐ 0.8 h after dosing; in contrast, after the morning dose the mean peak concentration occurred at 4.5 +/‐ 0.8 h. However, the mean 'steady‐ state' concentrations during the two dose intervals were not significantly different. Thus circadian variations in plasma drug concentrations do occur in patients taking maintenance theophylline therapy: differing rates of absorption may account for the observed pattern.

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