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

Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables.
Funder: Lady Davis Institute of the Jewish General Hospital
Funder: Canadian Foundation for Innovation
Funder: NIH Foundation
Funder: Fonds de Recherche Québec Santé (FRQS)
Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4)
Funder: Jewish General Hospital Foundation
Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062
Funder: Public Health Agency of Canada
Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582
Funder: Calcul Québec and Compute Canada
Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020
Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380
Funder: State of Saarland
Funder: Dr. Rolf M. Schwiete Foundation
Funder: Munich Clinician Scientist Programm
Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021
Funder: Federal Ministry of Education and Research
Funder: Leenaards Foundation
Funder: Santos-Suarez Foundation
Funder: Carigest
Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”
Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency)
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.