Central role of glycosylation processes in human genetic susceptibility to SARS-CoV-2 infections with Omicron variants

The host genetics of SARS-CoV-2 has previously been studied based on cases from the earlier waves of the pandemic in 2020 and 2021, identifying 51 genomic loci associated with infection and/or severity. SARS-CoV-2 has shown rapid sequence evolution increasing transmissibility, particularly for Omicron variants, which raises the question whether this affected the host genetic factors. We performed a genome-wide association study of SARS-CoV-2 infection with Omicron variants including more than 150,000 cases from four cohorts. We identified 13 genome-wide significant loci, of which only five were previously described as associated with SARS-CoV-2 infection. The strongest signal was a single nucleotide polymorphism (SNP) intronic of ST6GAL1, a gene affecting immune development and function, and connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. We also found further evidence for an involvement of blood group systems in SARS-CoV-2 infection, as we observed association 1) for a different lead SNP in the ABO locus indicating a protective effect of blood group B against Omicron infection, 2) for the FUT2 SNP tagging secretor status also reported for SARS-CoV-2 infection with earlier variants, and 3) for the strongest expression quantitative trait locus (eQTL) for FUT3 (Lewis gene). Our study provides robust evidence for individual genetic variation related to glycosylation translating into susceptibility to SARS-CoV-2 infections with Omicron variants.