A new paper digs into OAS1, A prenylated dsRNA sensor protects against severe COVID-19:
Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response.
You can find the SNP in you 23andMe raw data (unless you are on the recent chip; I looked for a tag variant but found none). If I’m reading the paper correctly, having the AA genotype increases your risk of severe COVID-19 by an odds of 1.58, all things equal. Not crazy bad, but not great either. The haplotype that carries the G allele in non-Africans seems to come from Neanderthals. In Africa, the ancestral G is the majority, though a minority of individuals are A, and that was passed on to Eurasians.
Here is a plot for the 1000 Genomes populations.
One thing I immediately noticed is that Peruvians have the highest frequency of the A allele in the dataset. Peru has had the highest COVID-19 death rate in the world, and its frequency of A means that a great number of people will be AA (the frequency of A squared).
I looked in Anders Bergstrom’s HGDP whole-genome data and found an interesting pattern in the frequencies of the G alelle:
| Population | Freq | Count | 2N |
| Karitiana | 0 | 0 | 22 |
| Pima | 0 | 0 | 26 |
| Surui | 0 | 0 | 16 |
| Yakut | 0 | 0 | 50 |
| Maya | 0.04762 | 2 | 42 |
| Oroqen | 0.1111 | 2 | 18 |
| Tujia | 0.1111 | 2 | 18 |
| Peruvian | 0.1118 | 19 | 170 |
| She | 0.15 | 3 | 20 |
| Cambodian | 0.1667 | 3 | 18 |
Three of the four populations with no copies of the protective G allele are indigenous to the Americas. The Maya, who are known to have European admixture, also have very low frequencies of the G allele. Now, it is true that East Asians also have low frequencies of the G allele (the Yakuts also lack it, so perhaps this was ancestral to Siberians?), but they may have other protective variants (or, suffered through an earlier coronavirus epidemic). I think OAS1 may turn out to be one of the loci that could be associated with a higher risk to severe COVD-19 in the New World.
I did 23andMe for me, my wife, my son, my daughter (but I don’t manage her results), my mother (1924-2013), my first cousin and another my first cousin’s husband (of course I manage other data) and frequently I was asked by 23&Me as to this last Giorgio Tognarelli. I never replied of course, but the data are that we all (mostly Tuscans, but my wife is from Sicily and my first cousin half Venetian) are AA, only Giorgio Tognarelli is AG.
Interesting. Spouse and I are AG, one kid is AA, one is GG. Great demonstration of Mendelian inheritance, I suppose. They’re in high school so I bored them both with an explanation of the genetics last night at dinner.
Thanks Razib, I was running out of ways to bore my kids at dinner (well, not really).
Interesting. I had a relatively mild case of Covid last December–two weeks of flu-like symptoms, no respiratory involvement. (I’m 64.) I just checked and I’m AG, so maybe that helped. My mother died of Covid early this year at 88, but she was tested with the new chip, so I can’t check her status.
Did FTDNA for myself, all my three living grandparents, the brother of my deceased paternal grandfather and another close relative on my paternal side (6 individuals in total). My paternal side is fully from the south-central part of Anatolia (within the historical Cappadocia region) and my maternal side is fully Balkan immigrants to Turkey from either northeastern Bulgaria or northern Greece. We are all AG except my maternal grandmother with all known ancestry from northern Greece, who is GG, and my paternal close relative, who is also GG. None of these 6 individuals have ever been infected with COVID-19 to my knowledge.
@Onur
Someone might have had an asymptomatic infection.
@DaThang
Someone might have had an asymptomatic infection.
Possible yes. Also, forgot to mention that my paternal grandmother died more than one year before the coronavirus outbreak, so we are actually comparing 5 tested individuals (who are still all alive BTW), not 6. Another point: I have not been in close contact with my tested paternal close relative since his genetic test, so do not know whether he has been infected or not during the pandemic, which leaves us with only 4 tested individuals for comparison, one of them GG (my maternal grandmother) and the other three AG.
I found the SNP in both my mother’s and my Ancestry raw data. It turns out that my mother was AG but still died of Covid. So unsurprisingly, the G variant isn’t completely protective.
There is a potential gradient of G allele in Europe, with the Italians having more A. I wonder if the association with the disease severity is partly caused by higher severity of the disease in Italy.