A genetic variant protective against severe COVID-19 is inherited from Neandertals

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome-wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa.


Main text
Neandertals and Denisovans are archaic hominin groups that became extinct about 40,000 years ago (Higham et al. 2014). They have a biological impact on human physiology today through genetic contributions to modern human populations that occurred during the last tens of thousands of years of their existence (e.g., Simonti et al. 2016, Dannemann andKelso 2017). Several of these contributions affect genes involved in the immune system (e.g., Laurent et al. 2011, Quach et al. 2016). In particular, variants at several loci containing genes involved in innate immunity come from Neandertals and Denisovans, for example toll-like receptor gene variants which decrease the susceptibility to Helicobacter pylori infections and increase the risk for allergies (Dannemann et al. 2016).
Recently, it was shown that a region on chromosome 3 harbors the major genetic risk locus for becoming critically ill upon infection with the novel coronavirus SARS-CoV-2 (Ellinghaus et al. 2020) and that the haplotype that confers the risk was contributed by Neandertals to modern humans (Zeberg and Pääbo 2020). This haplotype reaches carrier frequencies of up to ~65% in South Asia whereas it is almost absent in East Asia and occurs at ~16% in Europe. Thus, although this haplotype is detrimental for its carriers during the current pandemic, it has likely been beneficial in earlier times in South Asia, perhaps by conferring protection against other pathogens.
A new study from the GenOMICC consortium, which includes 2,244 critically ill COVID-19 patients and controls (Pairo-Castineira et al. 2020), identifies three new loci with genome-wide significant effects in addition to the risk locus on chromosome 3 located on chromosomes 12, 19 and 21. To test if any of these loci carry variants derived from Neandertals, we investigated if alleles of the index variants at these loci co-segregate in the population with alleles of single nucleotide polymorphisms (SNPs) that match three high-quality Neandertals genomes, while being absent in the genomes of 108 African Yoruba individuals (r 2 > 0.75 in all genomes of the 1000 Genomes Project). No SNPs fulfilling these criteria were found in two of the novel loci whereas 43 such SNPs exists at the chromosome 12 locus.
To further investigate this locus, we used the round 4 (alpha) release of the COVID-19 Host Genetics Initiative (HGI) (covid19hg.org) to analyze 35 SNPs that are significantly associated with severe COVID-19 and have been scored in the archaic genomes (Table S1) generation. Under these assumptions, we exclude that it derives from the common ancestor (p = 1.1e- 10) and conclude that this region entered the human gene pool from Neandertals. In agreement with this, a previous study (Mendez et al. 2013) has described gene flow from Neandertals in this region. We find that the index allele, i.e. the Neandertal allele with the greatest association with severe COVID-19 (rs4766664), occurs in all populations in Eurasia and Americas at frequencies that often reach and exceed 30% (Fig. 2).
The Neandertal haplotype protective against severe COVID-19 is located in a region in chromosome 12 that contain the three genes OAS1, OAS2 and OAS3, all of which encode oligoadenylate synthetases. To investigate which of these genes might be involved in the protection against severe COVID-19, we plot the genomic location of the OAS genes below the p-values for the association and the introgressed Neandertal haplotype (Fig. 1). The association (p<1e-6) overlaps all three OAS genes. The SNPs with the most significant associations (p<5e-8) are situated in the 3'-end of OAS1 and in OAS3, and thus these two genes are most likely to be involved in the protective effect(s) of the Neandertal haplotype.
There are several SNPs on the Neandertal haplotype, which stand out as potentially functionally important in this region. One SNP (rs10774671) has been noted to affect a splice acceptor site (Sams et al. 2016). The most common allele at this SNP is derived and alters splicing of the OAS1 transcript that produces an ancestral protein isoform (p46) to several alternative transcripts (Li et al. 2017). The ancestral isoform, preserved in Neanderthals, has been shown to have a higher enzymatic activity After these groups came into contact and fused ~50,000 years ago, they became exposed to novel pathogens. Some of the variants contributed by Neandertals rose to high frequencies either locally, as is the case in South Asia for the Neandertal haplotype on chromosome 3 (Zeberg and Pääbo 2020), or almost everywhere in Eurasia, as is the case for the Neandertal haplotype on chromosome 12 (Fig. 2).
With almost the entire world population now exposed to the novel SARS-CoV-2, the former haplotypes turn out to be detrimental while the latter haplotype turns out to be beneficial. Unfortunately, the protection against severe disease conferred by the Neandertal OAS locus is substantially smaller than the increased risk conferred by the chromosome 3 locus.

Methods
The index variants for the three novel loci (rs10735079, rs2109069, rs2236757) were obtained from GenOMICC (Pairo-Castineira et al. 2020). The regional summary statistics from the round 4 (alpha) release of the meta-analysis carried out by the COVID-19 Host Genetics Initiative (https://covid19hg.org/ results) was used to analyze the chromosome 12 locus. Linkage disequilibrium was calculated using    Table S1. Genome-wide significant variants (p < 5e-8) on chromosome 12. Figure S1. Diagnostic Neandertal variants and their pairwise linkage disequilibrium in Europeans. Table S1. Genome-wide significant variants (p < 5e-8) on chromosome 12. Red marks the minor allele which in all cases shown is protective. Note that the human reference genome carries the Neandertal