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Genetic mechanisms of critical illness in Covid-19

Our take —

This genome-wide association study among people primarily of European ancestry compared over two thousand critically ill COVID-19 patients to controls from several population-based cohorts. The authors replicated an association between severe illness and a genetic variant on Chromosome 3 (at 3p21.31) previously observed in other studies, and identified novel associations between several other genes and severe COVID-19. A Mendelian randomization study provided some evidence that severe COVID-19 is linked with lower IFNAR2 expression (involved in the antiviral defense mechanism of type I interferon signaling, the suppression of which has been previously implicated in severe COVID-19) and higher TYK2 expression (which may promote inflammatory lung injury). The study used population-based controls with no prior positive SARS-CoV-2 test, which makes unmeasured confounding likely. The results, if replicated elsewhere using non-critically ill COVID-19 patients as controls, may lead to development of therapeutic approaches to stimulate interferon activity and suppress harmful inflammation.

Study design

Case-Control, Other

Study population and setting

This was a genome-wide association study (GWAS) comparing genetic variants from 2,244 critically ill COVID-19 patients from 208 UK intensive care units to variants from ancestry-matched controls (5:1) in UK Biobank, a large population-based cohort. Potential controls were excluded if they had any record of a positive test for SARS-CoV-2. Ancestry was inferred using principal components analysis with a population reference from the 1000 Genomes Project. GWAS was performed separately by ancestry group. Tests for association with COVID-19 status were performed via multivariable logistic regression with the covariates sex, age, residential deprivation score, and the first 10 genomic principal components. Replication was attempted using a meta-analysis of data from the COVID-19 Host Genetics Initiative (2,415 hospitalized COVID-19 cases; 477,741 population-based controls). Two-sample Mendelian randomization was employed to assess the causal effects of RNA expression of several genes on the risk of severe COVID-19. The authors additionally performed a transcriptome-wide association study (TWAS) testing for links between GWAS results and tissue-specific (lung and whole blood) gene expression.

Summary of Main Findings

There were 15 independent associations between genetic variations and COVID-19 case status that had genome-wide significance (p < 5 x 10−8); of these, 8 were validated in GWAS using additional sources of population-based controls and thus included in replication analysis. Five of the 8 associations were replicated with statistical significance; these were found in loci on chr3 at 3p21.31 (odds ratio (OR): 2.14, p= 4.77 x 10-30), chr12 near the OAS gene cluster (OR: 1.59, p 1.65 x 10^−8), near TYK2 on chr19 (OR: 1.40, p: 2.3 10^−8), in DPP9 on chr19 (OR: 1.36, p 3.98 x 10^−8), and on chr21 containing the gene IFNAR2 (OR: 1.28, p 4.99 x 10^−8). A list of target genes was assessed in Mendelian randomization for possible effects on severe COVID-19; low expression of IFNAR2 showed statistically significant association with severe disease. Transcriptome-wide Mendelian randomization on unselected genes yielded no significant associations after adjustment for multiple tests; the smallest p-value (0.00049) was observed for an association between higher expression of TYK2 and severe disease. Both the IFNAR2 and TYK2 associations were replicated with statistical significance in an external dataset. In TWAS results, five genes had genome-wide differences in expected expression between cases and controls: CCR2, CCR3, CXCR6, and MTA2B from lung tissue; and OAS3 from whole blood.

Study Strengths

The COVID-19 cases were drawn from an existing network of ICUs in the UK and thus represented a well-defined group of critically ill patients, which better represents the outcome of interest (severe disease) than other methods of case selection (e.g., all hospitalized cases). The authors attempted to replicate their results using multiple independent control groups.


Control groups were drawn from population-based cohorts that differed from COVID-19 cases with respect to ancestry, demographic variables, and comorbidities; this may have introduced confounding of the variant-outcome associations. For example, if controls were less likely to have been exposed to SARS-CoV-2 than cases due to occupational or sociodemographic differences, effect estimates would be biased. This confounding is likely given the observed genetic correlations with educational attainment. Moreover, potential controls with any prior positive SARS-CoV-2 test were excluded, further confusing the contrast between cases and controls (i.e., cases had critical illness, whereas controls may not have ever been exposed to SARS-CoV-2). The study population of critically ill COVID-19 cases was not well described and its characteristics were not reported in detail, which limits interpretation of the observed associations. One of the assumptions of Mendelian randomization (that the genetic variant can only influence the outcome through the exposure of interest) appears to have been violated in the results for IFNAR2, which may have biased the effect estimate in an unknown direction. Finally, the study population was predominantly of European ancestry, limiting generalizability of results.

Value added

This GWAS confirms prior evidence for associations between genetic variants and severe disease, and adds novel evidence for associations that are amenable to replication in future analyses and may provide the basis for therapeutic interventions.

This review was posted on: 19 February 2021