LINK BETWEEN COVID-19 AND GENETIC VARIATIONS EXAMINED

Link between COVID-19 and genetic variations examined

An international collaboration between biobanks has challenged a previous finding on a potential genetic basis for COVID-19 severity

Research must use rigorous study design principles and properly control for ancestry differences as these greatly impact the frequency of gene variants.

In October 2020, a large, multinational research study led by Qian Zhang, of New York’s Rockefeller University, showed that some severe COVID-19 cases could be explained by hereditary mutations in genes that modulate important immune system pathways. Another large collaboration which used data from four independent COVID-19 biobanks from across the world sought to replicate these findings, but found that the original study’s results did not hold up. The new analysis found no link between severe COVID-19 and mutations in the genes identified in the earlier study.

Type I IFNs are polypeptides secreted by infected cells that modulate different elements of immunity. Inherited mutations in genes encoding proteins or polypeptides, such as those involved in type I IFN immunity, can result in non-functional proteins. In their study, Zhang et al. identified 13 variations in type I IFN-related genes that were predicted to cause a loss of function, and they assessed that as many as 3.5% of severe COVID-19 cases could be associated with changes in these 13 genes.

As researchers race to identify predictors of COVID19 severity and potential avenues for treatment, one study’s newly identified link between genetic variations and COVID19 outcomes has been contested by a more recent finding.

Following this, 52 researchers across six countries pooled data on 1,864 participants with COVID-19—713 severe cases and 1,151 mild cases—and 15,033 healthy controls. The genome and exome data were obtained from biobanks in the United States, Canada, Saudi Arabia, and Qatar. The researchers found just one instance of one of the 13 previously identified predicted loss-of-function variants in this data, and they saw no greater incidence of the predicted loss-of-function variants in severe COVID-19 cases compared to mild cases or uninfected people.

In the May 2021 study, results are corroborated by another analysis performed on data obtained from the UK Biobank, in which a comparison of 1,184 COVID-19 cases and 422,318 controls “showed no association between [predicted loss-offunction] variants in these genes.”

KAIMRC’s Manal Alaamery, who worked on the study, says that “the beauty of this paper is really the power of collaboration,” both on a national level within Saudi Arabia and internationally. In their paper, the team conclude that research along these lines must use rigorous study design principles and properly control for ancestry differences, as these greatly impact the frequency of gene variants. Further research projects will continue to investigate links between COVID-19 and genetics and could reveal potential therapeutic targets.

Povysil, G., et al. Rare loss-of-function variants in type I IFN immunity genes are not associated 1 with severe COVID19. Journal of Clinical Investigation131, e147834 (2021). Zhang Q et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, eabd4570 (2020)