A Neanderthal OAS1 isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies

Abstract

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to confounding and reverse causation. We began by identifying the genetic determinants of 955 circulating proteins in up to 10,708 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphisms near the gene encoded by the circulating protein. We then undertook an MR study to estimate the effect of these proteins on COVID-19 susceptibility and severity using the Host Genetics Initiative. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 2,972 cases / 284,472 controls; OR = 0.48, P = 7x10-8), COVID-19 hospitalization (N = 6,492 / 1,012,809; OR = 0.60, P = 2x10-7) and COVID-19 susceptibility (N = 17,607 / 1,345,334; OR = 0.81, P = 6x10-5). Results were consistent despite multiple sensitivity analyses probing MR assumptions. OAS1 is an interferon-stimulated gene that promotes viral RNA degradation. Other potentially implicated proteins included IL10RB. Available medicines, such as interferon-beta-1b, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.

Local adaptation and archaic introgression shape global diversity at human structural variant loci

“…Our findings thus suggest that persisting archaic introgressed haplotypes provided a reservoir of functional variation to the ancestors of CDX and KHV that proved adaptive during a period of environmental change, for example in response to local pathogens (Rasmussen et al, 2015). Recent reports that Neanderthal-introgressed sequences mediate individual outcomes of SARS-CoV-2 infections to this day lend plausibility to this hypothesis Pääbo, 2020a, 2020b) (Zhou et al, 2020), as does polygenic evidence of adaptation in response to ancient viral epidemics, including in East Asia (Souilmi et al, 2021).…”

Preexisting and inducible endotoxemia as crucial contributors to the severity of COVID-19 outcomes

“…LPS levels were investigated in a prospective study on 19 patients with severe pulmonary forms of COVID-19; almost 90% of them had increased LPS levels—40% demonstrated high and 30% demonstrated very high endotoxin levels [ 9 ]. Application of mendelian randomization using 6,492 hospitalized cases and over 1 million controls demonstrated that serum LBP levels strongly correlate with the hospitalization rate of COVID-19 patients [ 10 ]. The plasma levels of LBP were also investigated in 39 hospitalized patients with severe COVID-19 with significant cardiac pathology; these levels were initially high and remained high during hospitalization [ 11 ].…”

Host transcriptional response to SARS-CoV-2 infection in COVID-19 patients

“…We identified a few other genes involved in viral response that were upregulated in patients with active COVID-19 infection. Increased OAS1 levels confer protection against severe COVID-19 [18] and this family of antiviral genes has been shown to be associated with the host response [19].…”