Exome-wide association study to identify rare variants influencing COVID-19 outcomes:Results from the Host Genetics Initiative

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.

Rights

This content is not covered by the Open Government Licence. Please see source record or item for information on rights and permissions.

Cite as

Downloadable citations

Identifiers

DOI

https://doi.org/10.1371/journal.pgen.1010367

Repository URI

https://www.research.ed.ac.uk/en/publications/fd2f1664-54b4-48e6-9520-23766c98e522