A genomic region associated with protection against severe COVID-19 is inherited from Neandertals

Abstract

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

Keywords: COVID-19; Neandertals; OAS1; SARS-CoV-2.

Fig. 1.

Genetic variants associated with COVID-19 hospitalization at the OAS locus. Variants marked in red have P values less than 1e-5. In Europeans, they are in LD with the index variant (r² ≥ 0.8), forming a haplotype (black bar) with the genomic coordinates chr12: 113,350,796 to 113,425,679. P values are from the HGI (24), excluding the 23andMe data for which only sparse SNP data are available. The x axis gives hg19 coordinates; genes in the region are indicated below. The three OAS genes are transcribed from left to right. Yellow dots indicate rs10735079 (right, the GenOMICC index SNP) and rs1156361 (left, typed by the Human Origins Array).

Fig. 2.

Phylogeny relating DNA sequences associated with COVID-19 severity on chromosome 12. Haplotypes from three Neandertal genomes, the Denisovan genome, and haplotypes seen more than 20 times in individuals in the 1000 Genomes Project are included. The colored area indicates haplotypes that carry the protective allele at rs1156361. The tree is rooted with the inferred ancestral sequence from Ensembl (46). Six heterozygous positions in the archaic genomes were excluded. Haplotypes XXIX and XXX are partially made up of Neandertal-like DNA sequences due to recombination events.

Fig. 3.

Geographic distribution of the allele indicative of the Neandertal haplotype protective against severe COVID-19. Pie charts indicate minor allele frequency in red at rs1156361. Frequency data are from the 1000 Genomes Project (23). Map source data are from OpenStreetMap.

Fig. 4.

Frequencies across time of two Neandertal haplotypes associated with COVID-19 severity. Frequencies for rs1156361 at the OAS locus on chromosome 12 (A) and rs10490770 at the chromosome 3 locus (B). Error bars indicate SE (Wilson scores). Time periods are indicated in years before present (bp). Ancient data are from a compiled dataset (42), and present-day data are from the 1000 Genomes Project (23).