Genetic underpinnings of severe, life-threatening COVID-19 uncovered

The propensity of the novel coronavirus disease (COVID-19) to develop into a severe and life-threatening disease appears to be influenced by genetics, according to the GenOMICC* study, whose results were recently presented at the eCritical Care Reviews Meeting 2021 (eCCR21).

“There is always variability in susceptibility to infection,” said Kenneth Baillie, leader of GenOMICC. “There are multiple biological factors underlying that, but some of it is genetic.”

This analysis sought to identify key genes and molecules regarding COVID-19 and open up new therapeutic avenues.

The researchers first searched for genetic signals in 2,244 critically ill COVID-19 patients, enrolled from 208 UK intensive care units. Using ancestry-matched controls, while excluding individuals with known COVID-19 exposure, a genome-wide association study (GWAS) identified 15 independent genetic signals, with p-value <5×10^–8. [Nature 2020;doi:10.1038/s41586-020-03065-y]

Of these, eight were successfully validated in a subsequent GWAS that used two independent population genetic studies as controls.

To further refine the list of potential genetic targets, the researchers replicated their findings in a meta-analysis of data from 2,415 hospitalized COVID-19 patients, retrieved from the COVID-19 Host Genetics Initiative, along with 1,128 cases from 23andMe. A total of 477,741 and 679,531 unexposed controls were also enrolled from the respective data sources.

Ultimately, five genetic signals emerged significant in both the initial GWAS and subsequent replication studies. These included specific loci in or around the OAS gene cluster, and the TYK2, DPP9, CCR2, and IFNAR2 genes.

“Our findings reveal that critical illness in COVID-19 is related to at least two biological mechanisms: innate antiviral defences, which are known to be important early in disease (IFNAR2 and OAS genes), and host-driven inflammatory lung injury, which is a key mechanism of late, life-threatening COVID-19 (DPP9, TYK2, and CCR2),” the researchers explained.

Mendelian randomization further revealed a causal effect of the IFNAR2 gene on the likelihood of developing severe or life-threatening COVID-19. Particularly, enhanced expression of its resulting interferon receptor subunit protein significantly reduced the odds of such an outcome.

While the other genetic loci failed to demonstrate significance in Mendelian randomization, their known biological functions nevertheless support their potential roles in COVID-19 disease course. OAS genes, for instance, form part of the pathway that culminates in the activation of RNAse L, an enzyme that can degrade double-stranded RNA, which coronaviruses use as a replication intermediate. [Exp Mol Med 2015;47:e144; J Virol 2012;86:5808-5816]

“Genetics can potentially lead us to new treatments. That’s fundamentally the reason for doing all of this work and that’s why clinicians should be interested,” said Baillie, referring to the GenOMICC study.

“This is the work of an absolutely colossal number of people who really did all work very, very hard to make it happen,” he added.

*Genetics of mortality in critical care