- 15 independent association signals were genome-wide significant at p < 5 * 10^-8
- Eight of these were successfully validated in GWAS using two independent population genetic studies as controls and hence were taken forward for replication
- A sex-specific GWAS among this group found no sex-specific associations
- Trans-ethnic meta-analysis did not reveal additional associations

GWAS Results

- Replication was sought in a meta-analysis of data from 2415 hospitalised
Covid-19 cases and 477741 population controls from the Covid-19 Host
Genetics Initiative (HGI, mixed ancestry, with UK Biobank cases and
controls excluded) and 1128 cases and 679531 controls in the 23andMe
Inc “broad respiratory phenotype” (EUR ancestry), which includes
cases reported being placed on a ventilator, being administered oxygen,
or having pneumonia versus controls who did not report positive tests
- In addition to the locus on chr3 already reported, we found robust replication for the novel associations in four loci from GenOMICC: a locus on chr12 in the OAS gene cluster, near TYK2 on chr19, in DPP9 on chr19, and a locus on chromosome 21, containing the gene IFNAR2
- Three variants, all in a region of chromosome 6 in which population stratification is difficult to control, did not replicate
- To increase power for exploratory analyses, inverse-variance
meta-analysis was performed. This revealed one additional (unreplicated) locus in CCHCR1 at genome-wide significance

Replication

* Mendelian randomisation provides evidence for a causal relationship between an exposure variable and an outcome, given a set
of well-characterised assumptions.

- Researchers  employed two-sample summary-data Mendelian randomisation to assess the evidence in support of causal effects of RNA expression of various genes on the odds of critical Covid-19.
- It was found that IFNAR2 expression may be linked to critical illness
- Researchers preformed transcriptome-wide Mendelian randomisation
to quantify support for unselected genes as potential therapeutic targets.
- No genes were statistically significant
- Results were replicated with similar findings

Mendelian Randomization

- A transcriptome-wide association study (TWAS) to link GWAS results to tissue-specific gene expression data was performed
- 5 genes were discovered with genome-wide significant differences in predicted expression compared to controls
- This included 4 genes with genome-wide significant differences in predicted expression compared to controls
- 3 on chr3: CCR2, CCR3, CXCR6
- 1 on chr5: MTA2B
- MAIC used to put results in context

Transcriptome-Wide Association Study

- HDL method was used to provide an initial estimate of the SNP-based heritability for severe COVID-19 to be 0.065
- No significant heritability found in two additional analyses
- Significant positive genetic correlations were detected for a number of adiposity phenotypes including body mass index and leg fat
- Consistent with GWAS results from other infectious and inflammatory diseases, there was a significant enrichment of strongly associated
variants in promoters and enhancers, particularly those identified by
the EXaC study as under strong evolutionary selection
- The strongest tissue type enrichment was in spleen (which may reflect enrichment in immune cells), followed by pancreas

Genetic Correlations

The GenOMICC genome-wide association study (GWAS) investigated the genetic mechanisms of critical COVID-19. The study's cohort included 2,734 unique cases representative of the critically ill UK population. DNA was extracted from whole blood to obtain high-quality array-based genome-wide genotypes. For this multi-ancestry cohort, imputation was performed using the TOPMed reference panel, and ancestry-matched controls were selected from the UK Biobank. The primary analyses focused on the largest ancestry group, which contained 1,676 individuals of European descent (EUR).

Michigan State University

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OVERVIEW (ABSTRACT)
- In COVID-19, host-mediated lung inflammation is the primary critical illness driving mortality
- Genetic variants in hosts with critical illness may reveal mechanistic targets for vaccine development / therapeutic development
- This article focuses on the results of the GenOMICC genome-wide association study (GWAS)
- Novel genome-wide significant associations are identified and replicated
- There is evidence to support a causal link from low expression of IFNAR2 and high expression of TYK2 to life-threatening disease
- The monocyte/macrophage chemotactic receptor CCR2 is associated with severe COVID-19
- Both mechanisms proposed may be amenable to targeted treatment with existing drugs
- More randomized clinical trials are needed before changing clinical practice

Genetic mechanisms of critical illness of Covid-19

https://www.nature.com/articles/s41586-020-03065-y

Genetic mechanisms of critical illness in Covid-19

GenOMICC GWAS Cohort for Critical COVID-19

Genetic evidence supporting a therapeutic target substantially improves the probability of successful drug development, as genetic variation can be used to draw causal inferences. Findings reveal that critical illness in Covid-19 is related to at least two biological mechanisms: innate antiviral defences, which are important early in the disease (e.g., IFNAR2 and OAS genes), and host-driven inflammatory lung injury, a key mechanism of late, life-threatening Covid-19 (e.g., DPP9, TYK2, and CCR2). Mendelian randomisation results implying a causal role for IFNAR2 and TYK2 are statistically significant in confirmatory analyses, and the association with critical illness for genotype-inferred CCR2 expression is particularly strong in lung tissue. Additionally, the ABO locus was previously associated with Covid-19 but was not genome-wide significant in the GenOMICC critically ill cohort. Interestingly, patients admitted to intensive care units in the UK during the first wave of Covid-19 were, on average, younger and less burdened by comorbid illness than the broader hospitalised population. Further studies are urgently needed to deepen these findings.

Discussion of Genetic Findings in Critical Covid-19

There are at least two distinct biological components to COVID-19 mortality risk: susceptibility to viral infection and the propensity to develop harmful pulmonary inflammation. Both components are inheritable and associated with specific genetic variants. For instance, the genetic locus 3p21.31 has been repeatedly associated with hospitalization. Critical COVID-19 respiratory failure has a distinct pathophysiology characterized by profound pulmonary inflammation, diffuse alveolar damage, macrophage influx, and microthrombus formation, and it is highly responsive to corticosteroid therapy. To better understand these underlying host-driven inflammatory mechanisms, researchers utilized GenOMICC data to perform a genome-wide association study (GWAS).

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