Since much earlier in the pandemic, scientists have been busily investigating how patient genetics influence the severity of a SARS-CoV-2 infection, exposing the inherited factors that appear to protect people from – or alternatively predispose them to – severe manifestations of the resulting disease.
Now that effort looks to have uncovered a promising new lead. Building upon findings from late 2020 that revealed numerous genetic mechanisms linked to life-threatening cases of COVID-19, an international team of researchers has identified a specific gene variant that can confer protection from critical illness.
In 2020, an analysis of genetic data primarily obtained from European people found that a locus of genetic variants in the OAS1/2/3 gene cluster was linked with several antiviral mechanisms. These variants conferred an approximately 23 percent reduced risk of becoming critically ill in cases of SARS-CoV-2 infection, in addition to other factors tied to virus susceptibility.
Nonetheless, it was unclear exactly what it was within this region of largely Neanderthal-inherited DNA that prompted the boosted protection against the coronavirus, meaning a causal gene or genes still remained to be identified – until now.
In a new study, researchers compared information from people of different ancestries – looking at genetic datasets of people from both African and European lineages.
The scientists' goal was to see if they could narrow the search further within the OAS1/2/3 cluster and determine the same protective signal in the comparatively shorter haplotypes of African people – who don't carry the same complicated influx of Neanderthal and Denisovan genes in their own DNA, which makes identifying potentially causal variants much more problematic.
The approach worked. In an analysis of 2,787 COVID-19 cases alongside the genetic data of 130,997 individuals of African ancestry, the researchers identified an allele in the gene rs10774671 that confers protection against COVID-19 hospitalization in individuals of African ancestry, corresponding to what had previously been seen in Europeans.
"The fact that individuals of African descent had the same protection allowed us to identify the unique variant in the DNA that actually protects from COVID-19 infection," says first author and genomics researcher Jennifer Huffman from the VA Boston Healthcare System.
The variant in question – called rs10774671 G – confers protection against COVID-19 severity independently of other associated alleles in non-African populations, the researchers say, and their analysis suggests it is likely to be the only causal variant behind the protection effect.
Given that African ancestries do not usually feature Neanderthal haplotypes – unlike European populations, who adopted Neanderthal genes through breeding with Neanderthals during their long migration out of Africa – the common rs10774671 G variant exists today in both Africans and Europeans "as a result of their inheritance from the ancestral population common to both modern humans and Neanderthals," the researchers write in their paper.
"Such variants have existed in modern humans on the order of approximately half a million years and therefore co-segregate with different variants than when they are derived from gene flow from Neanderthals into modern humans that occurred about 60,000 years ago."
While the variant appears to have been carried by humans for a very long time, it wouldn't have been easy to find, given how complex genetic analyses like this are – unless populations of different kinds are compared, that is.
"This study shows how important it is to include individuals of different ancestries," says senior researcher and evolutionary geneticist Hugo Zeberg from the Karolinska Institute in Sweden.
"If we had only studied one group, we would not have been successful in identifying the gene variant in this case."
While there's much more to yet study around rs10774671 G, the researchers suggest the protective effect comes about due to the variant's effect on the OAS1 gene, encoding a longer OAS1 protein that is more effective at breaking down SARS-CoV-2 than the unaltered form.
If they're right, the insight could be an important step toward new kinds of treatment that may boost immune response in a similar way.
"That we are beginning to understand the genetic risk factors in detail is key to developing new drugs against COVID-19," says senior researcher and geneticist Brent Richards from McGill University in Canada.
The findings are reported in Nature Genetics.