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).

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The number of UK full-time university students engaging in term-time employment (TTE) is rising. Students engaging in TTE have previously been found to achieve less well academically than those who do not. This study aimed to explore patterns of TTE and academic achievement of undergraduates at a large UK higher education institution. Self-reported TTE hours were matched to attainment data for 1304 undergraduate students in levels 1-4 of study (SQCF levels 7-10). The majority of students in TTE (71%, n=621) reported undertaking TTE to cover essential living expenses. Compared to students not undertaking TTE, attainment was significantly better at low levels of TTE (1-10 hours), and only significantly worse when TTE was >30 hours/week. This pattern was magnified when job type was taken into account – students employed in skilled roles for ≤10 hours/week on average attained grades 7% higher than those not in TTE; students working >10 hours/week in unskilled positions showed a mean 1.6% lower grade. The impact of ‘academic potential’ (measured via incoming UCAS tariff) was accounted for in the model. The finding that students engaging in some categories of TTE achieve better academic outcomes than their non-employed peers is worthy of further investigation. This study is unable to provide direct evidence of possible causation, but would tentatively suggest that students may benefit from taking on 10 or fewer hours of TTE per week.

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