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

The host genetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have 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 of 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 in an intron of ST6GAL1, a gene affecting immune development and function, connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. Our study provides robust evidence for individual genetic variation related to glycosylation, translating into susceptibility to SARS-CoV-2 infections with Omicron variants.

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Journal
Nature Genetics
Published
2026-01-22
DOI
https://doi.org/10.1038/s41588-025-02484-9
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
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article

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

Niklas Andersson, Christina Mikkelsen, Lampros Spiliopoulos, Lea Arregui Nordahl Christoffersen et al.
Nature Genetics
SARS-CoV-2 and COVID-19 Research
article

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

Niklas Andersson, Christina Mikkelsen, Lampros Spiliopoulos, Lea Arregui Nordahl Christoffersen, Geller Frank, Anders Hviid, Katerina Nastou, Niels Tommerup, Angus C. Burns, Lasse Boding, Peter Bager, Susanne Dam Nielsen, Claus Henrik Nielsen, Kathrine Agergård Kaspersen, Vilma Lammi, Jesse Tyler Valliere, Kirsten Grønbæk, Khoa Manh Dinh, Sofie Bliddal, Erik Abner, Ole Birger Pedersen, Morten Rasmussen, Christian Erikstrup, Hanna M. Ollila, Ulla Feldt-Rasmussen, Ria Lassaunière, Nanna Brøns, Bitten Aagaard, Erik Sørensen, Karina Banasik, Celia Burgos Sequeros, Jacqueline M. Lane, Liam Quinn, Henrik Ullum, Maria Didriksen, Sisse Rye Ostrowski, Bjarke Feenstra, Janna Nissen, FinnGen, Henriette Svarre Nielsen, Søren Brunak
article en

Abstract

The host genetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have 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 of 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 in an intron of ST6GAL1, a gene affecting immune development and function, connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. Our study provides robust evidence for individual genetic variation related to glycosylation, translating into susceptibility to SARS-CoV-2 infections with Omicron variants.

Nature GeneticsVol. 58(2)
Statens Serum Institut (DK), Broad Institute (US), University of Copenhagen (DK), University of Helsinki (FI), Harvard University (US), Novo Nordisk (Denmark) (DK), Aarhus University (DK), Aalborg University Hospital (DK), Mental Health Services (DK), Amager Hospital (DK), Novo Nordisk Foundation (DK), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Massachusetts General Hospital (US), Institute for Molecular Medicine Finland (FI), Zealand University Hospital Køge (DK), University of Tartu (EE), Danmarks Nationalbank (DK)
Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Biogen, Celgene, Aarhus Universitet, Aarhus Universitetshospital, Maze Therapeutics, European Commission, Eesti Teadusagentuur, Novo Nordisk, NordForsk, Danmarks Frie Forskningsfond, Rigshospitalet, Tartu Ülikool, Novo Nordisk Fonden, Business Finland, National Institutes of Health, Genentech, Abbott Diagnostics, HORIZON EUROPE Framework Programme, Staatssekretariat für Bildung, Forschung und Innovation, Statens Serum Institut, Janssen Biotech
Good health and well-being
Openalex Percentile: Top 79%
SARS-CoV-2 and COVID-19 Research
DOIOpen Access PDFOpenAlex
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