Since the beginning of the COVID-19 pandemic, scientists have explored the biological and genetic elements influencing susceptibility to the virus. Several genomic regions associated with COVID-19 have now been identified. However, there’s a relative scarcity of in-depth research examining the direct causal links between specific genetic variations and predisposition to severe COVID-19.
For example, the OAS1/2/3 locus on chromosome 12 is identified as a COVID-19 risk factor, predominantly in European patients. A person inheriting a series of DNA variations in this region reduces their likelihood of falling critically ill due to the virus by 23%. The OAS1/2/3 locus is known to be associated with genes related to the immune system.
Nonetheless, identifying the exact protective genetic variation within this extensive DNA region proves challenging due to the sheer number of genes and genetic variants that it comprises.
The Study
A research paper published in Nature Genetics in 2022 sought to identify the causal single nucleotide polymorphisms (SNPs) that modulate an individual’s susceptibility to COVID-19. This expansive international metastudy was conducted by research teams from the Karolinska Institutet in Sweden, the Lady Davis Institute of the Jewish General Hospital in Canada, and the VA Boston Healthcare System in the U.S.
Within the scope of their research, the authors proposed a potential causal variant in the OAS1/2/3 locus, designated as rs10774671. Individuals possessing a specific allele of this variant produce a longer, more active form of the OAS1 enzyme, which is theorized to be more proficient at combating SARS-CoV-2.
To confirm that rs10774671 is the causal variant, the researchers aimed to recruit a participant cohort that carries this variant but not many nearby variants that may confound the results. Previous studies had traced the inheritance pattern of this DNA region back to Neanderthals after their migration from Africa. This led the researchers to focus their study on individuals with predominantly African ancestry who would possess the relevant DNA region with the rs10774671 but do not co-inherit potentially confounding variants.
Results
The research approach utilized six existing studies that examined COVID-19 severity, encompassing nearly 3,000 hospitalized COVID-19 patients of African ancestry and over 130,000 controls.
The researchers discovered that the rs10774671-G allele offered a similar level of protection against COVID-19 hospitalization to individuals of African ancestry as those of European descent. This consistent protection, irrespective of the presence of other variants in this region, suggests that rs10774671 is the causal variant that affects the body’s response to COVID-19 infection.
The authors emphasize that their study’s success depended significantly on examining a diverse range of individuals across various ancestries. This paper, therefore, provides compelling evidence of the importance of integrating diverse populations into all future genetic studies.
Explore your Genome!
Did you know you can use the Nebula Genome Browser (available with Deep and Ultra Deep WGS) to check whether you have protective variants?
- Go to the Genome Browser. In the top left corner of the genome browser, you can find a search bar.
- The authors identified multiple independent variants in OAS1 that contribute to protection. The rsID is rs10774671.
- Using the dbSNP database, you can find that the genome coordinates in the format [chromosome number][chromosome location] is 12:112919388 (GRCh38 reference genome).
- Copy-paste this location into the search bar and press enter.
- Copy-paste this location into the search bar and press enter.
- The genome browser will now zoom in on this location.
- Activate the “Center Line” in the bar at the top to better see the location that you are looking at.
- You should see stacked, gray stripes. Those are your DNA sequencing reads aligned to a reference genome sequence (colored letters above). If your DNA sequence matches the reference, then the stripes are gray. If the sequence is different from the reference, you will see various letters and symbols in different colors.
- For the variant rs10774671, you have a protective allele if you see a G. The chance of having G as the reference allele depends on your ancestry. Remember that the protective alleles are only extra protection! The group that doesn’t carry the protective allele has no greater risk than the general population.
Citation
Huffman JE, Butler-Laporte G, Khan A, Pairo-Castineira E, Drivas TG, Peloso GM, Nakanishi T; COVID-19 Host Genetics Initiative; Ganna A, Verma A, Baillie JK, Kiryluk K, Richards JB, Zeberg H. Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19. Nat Genet. 2022 Feb;54(2):125-127. doi: 10.1038/s41588-021-00996-8. Epub 2022 Jan 13. PMID: 35027740; PMCID: PMC8837537.
