Analysis of the Spectrum of ACE2 Variation Suggests a Possible Influence of Rare and Common Variants on Susceptibility to COVID-19 and Severity of Outcome

We demonstrate that the European populations slightly differ in alternative allele frequencies at the 2,754 variant sites in <i>ACE2</i> identified in the gnomAD database. We find that the Southern European population has a lower frequency of missense variants and slightly higher frequency of regulatory variants. However, we found no statistical support for the significance of these differences. We also show that the Russian population is similar to other European populations when comparing the frequencies of the <i>ACE2</i> variants. Evaluation of the effect of various classes of <i>ACE2</i> variants on COVID-19 outcome in a cohort of Russian patients showed that common missense and regulatory variants do not explain the differences in disease severity. At the same time, we find several rare <i>ACE2</i> variants (including rs146598386, rs73195521, rs755766792, and others) that are likely to affect the outcome of COVID-19. Our results demonstrate that the spectrum of genetic variants in <i>ACE2</i> may partially explain the differences in severity of the COVID-19 outcome.