No abstract

Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

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.