ABSTRACT
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights. Author SummaryCOVID-19 clinical outcomes vary immensely, but a patients genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isnt clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.
ABSTRACT
COVID-19 shows an unexplained, strong male bias for severity and mortality. Loss of Y (LOY) in myeloid cells is a risk factor candidate in COVID-19 because of associations with many age-related diseases and its effect on transcription of immune genes. We report the highest levels of LOY in cells that are crucial for the development of severe COVID-19 phenotype, such as low-density neutrophils, granulocytes, and monocytes reaching 46%, 32%, and 29%, respectively, from men with critical COVID-19 (n=139). LOY in sorted subpopulations of leukocytes correlated with increased thrombocyte count, thromboembolic events, invasive mechanical ventilation and a history of vessel disease. In recovered patients, LOY decreased in whole blood and peripheral blood mononuclear cells. Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, notably affecting HLA class I and II genes important for antigen presentation. The data support a link between LOY and emergency myelopoiesis as well as the role of LOY in modulation of COVID-19 severity. Our results might also be relevant for other viral infections showing similar male bias.