Canadian COVID-19 host genetics cohort replicates known severity associations

Abstract

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.

Fig 1. Genome-wide association study of hospitalization status in 8,474 HostSeq samples with COVID-19 from the March 2023 release (V9).

In the Manhattan plot, Y-axis indicates -Log10 p-values of regenie analysis for variants with MAF > 5%, X-axis indicates chromosomes. Variants falling in the GIAB difficult-to-sequence regions have been excluded. Grey horizontal line indicates genome-wide significance level of P < 5E-8. Chromosome 6 and chromosome 3 loci have been previously identified in HGI. In the corresponding QQ-plot, the X and Y axes indicate expected and observed -Log10 p-values, respectively (genomic control λ = 1.048).

Fig 2. Region plots for the top three loci from HGI7no compared with HostSeq.

Querying the three regions: a) chr3:45805277, b) chr6:41515629, c) chr21:33249643 in HGI7no (top row in each pane) with HostSeq (bottom row in each pane) shows similar patterns for two out of three loci (chr3:45805277, chr6:41515629). Plots were generated using myLocusZoom.

Fig 3. Within-HostSeq comparison of the three lead variants from HGI7no.

Examination of the three lead variants from HGI7no, depicting beta and SE for all N = 8,474 HostSeq samples and various stratifications of the HostSeq samples. The top panel shows results for all HostSeq samples passing QC. The last panel shows results from HGI7no. The panels in between show results for various stratifications of HostSeq including ancestry, sex, study, model and kinship. In the ‘model’ panel, ‘study-covariate’ indicates that HostSeq study centre was added as a categorical covariate to the main model (top panel). In the ‘kinship’ panel, ‘not-related’ indicates the subset that excludes samples within 2 degrees of relatedness as determined by KING. At the chromosome 3 locus all subsets, except for AFR, are consistent in sign of beta (i.e. effect direction). At the chromosome 6 locus, in addition to AFR, BQC19 differs from all other HostSeq subsets in sign of beta. The chromosome 21 locus is the most variable within HostSeq. Note that the X-axis scale varies among the three variants.