Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation. Author summary: Host genetics determine how human genetics contribute to the response to infectious disease. HostSeq is a Canada-wide effort to contribute to our understanding of host genetics for COVID-19. The HostSeq study involves genetic and clinical data from individuals who tested positive for SARS-CoV-2 across Canada. This work examines locations in the human genome that have been reported to be involved in severe COVID-19 worldwide and determines if we also see the involvement of those genomic locations in Canadians. This work also explores several 'genetic quantities' such as a determination of how much of COVID-19 severity is due to genetics in Canada. [ABSTRACT FROM AUTHOR]