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

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

doi:10.1038/s41588-025-02484-9

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

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

^*Corresponding author for this work

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.

Original language	English
Journal	Nature Genetics
Volume	58
Issue number	2
Pages (from-to)	299–306
Number of pages	21
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02484-9
Publication status	Published - Feb 2026

Keywords

COVID-19/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Glycosylation
Humans
Membrane Proteins/genetics
Mucin 5AC
Mucin-1/genetics
Polymorphism, Single Nucleotide
SARS-CoV-2/genetics

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Geller, F., Wu, X., Lammi, V., Abner, E., Valliere, J. T., Nastou, K., Burns, A., Rasmussen, M., Andersson, N. W., DBDS Genomic Consortium, Quinn, L., Aagaard, B., Banasik, K., Bliddal, S., Boding, L., Brunak, S., Brøns, N., Bybjerg-Grauholm, J., Christoffersen, L. A. N., ... Feenstra, B. (2026). Central role of glycosylation processes in human genetic susceptibility to SARS-CoV-2 infections with Omicron variants. Nature Genetics, 58(2), 299–306. https://doi.org/10.1038/s41588-025-02484-9

Geller, F , Wu, X, Lammi, V, Abner, E, Valliere, JT, Nastou, K, Burns, A, Rasmussen, M, Andersson, NW, DBDS Genomic Consortium, Quinn, L, Aagaard, B, Banasik, K , Bliddal, S, Boding, L, Brunak, S, Brøns, N, Bybjerg-Grauholm, J, Christoffersen, LAN , Didriksen, M , Dinh, KM, Erikstrup, C, Feldt-Rasmussen, U , Grønbæk, K, Kaspersen, KA, Mikkelsen, C , Nielsen, CH , Nielsen, HS , Nielsen, SD , Nissen, J, Sequeros, CB, Tommerup, N, Ullum, H, Estonian Biobank Research Team, FinnGen, Spiliopoulos, L, Bager, P, Hviid, A, Sørensen, E, Pedersen, OB, Lane, JM, Lassaunière, R, Ollila, HM, Ostrowski, SR & Feenstra, B 2026, 'Central role of glycosylation processes in human genetic susceptibility to SARS-CoV-2 infections with Omicron variants', Nature Genetics, vol. 58, no. 2, pp. 299–306. https://doi.org/10.1038/s41588-025-02484-9

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

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.",

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author = "Frank Geller and Xiaoping Wu and Vilma Lammi and Erik Abner and Valliere, \{Jesse Tyler\} and Katerina Nastou and Angus Burns and Morten Rasmussen and Andersson, \{Niklas Worm\} and \{DBDS Genomic Consortium\} and Liam Quinn and Bitten Aagaard and Karina Banasik and Sofie Bliddal and Lasse Boding and S{\o}ren Brunak and Nanna Br{\o}ns and Jonas Bybjerg-Grauholm and Christoffersen, \{Lea Arregui Nordahl\} and Maria Didriksen and Dinh, \{Khoa Manh\} and Christian Erikstrup and Ulla Feldt-Rasmussen and Kirsten Gr{\o}nb{\ae}k and Kaspersen, \{Kathrine Agerg{\aa}rd\} and Christina Mikkelsen and Nielsen, \{Claus Henrik\} and Nielsen, \{Henriette Svarre\} and Nielsen, \{Susanne Dam\} and Janna Nissen and Sequeros, \{Celia Burgos\} and Niels Tommerup and Henrik Ullum and \{Estonian Biobank Research Team\} and FinnGen and Lampros Spiliopoulos and Peter Bager and Anders Hviid and Erik S{\o}rensen and Pedersen, \{Ole Birger\} and Lane, \{Jacqueline M.\} and Ria Lassauni{\`e}re and Ollila, \{Hanna M.\} and Ostrowski, \{Sisse Rye\} and Bjarke Feenstra",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = feb,

doi = "10.1038/s41588-025-02484-9",

language = "English",

volume = "58",

pages = "299–306",

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T1 - Central role of glycosylation processes in human genetic susceptibility to SARS-CoV-2 infections with Omicron variants

AU - Geller, Frank

AU - Wu, Xiaoping

AU - Lammi, Vilma

AU - Abner, Erik

AU - Valliere, Jesse Tyler

AU - Nastou, Katerina

AU - Burns, Angus

AU - Rasmussen, Morten

AU - Andersson, Niklas Worm

AU - DBDS Genomic Consortium

AU - Quinn, Liam

AU - Aagaard, Bitten

AU - Banasik, Karina

AU - Bliddal, Sofie

AU - Boding, Lasse

AU - Brunak, Søren

AU - Brøns, Nanna

AU - Bybjerg-Grauholm, Jonas

AU - Christoffersen, Lea Arregui Nordahl

AU - Didriksen, Maria

AU - Dinh, Khoa Manh

AU - Erikstrup, Christian

AU - Feldt-Rasmussen, Ulla

AU - Grønbæk, Kirsten

AU - Kaspersen, Kathrine Agergård

AU - Mikkelsen, Christina

AU - Nielsen, Claus Henrik

AU - Nielsen, Henriette Svarre

AU - Nielsen, Susanne Dam

AU - Nissen, Janna

AU - Sequeros, Celia Burgos

AU - Tommerup, Niels

AU - Ullum, Henrik

AU - Estonian Biobank Research Team

AU - FinnGen

AU - Spiliopoulos, Lampros

AU - Bager, Peter

AU - Hviid, Anders

AU - Sørensen, Erik

AU - Pedersen, Ole Birger

AU - Lane, Jacqueline M.

AU - Lassaunière, Ria

AU - Ollila, Hanna M.

AU - Ostrowski, Sisse Rye

AU - Feenstra, Bjarke

PY - 2026/2

Y1 - 2026/2

N2 - 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.

AB - 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.

KW - COVID-19/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Glycosylation

KW - Humans

KW - Membrane Proteins/genetics

KW - Mucin 5AC

KW - Mucin-1/genetics

KW - Polymorphism, Single Nucleotide

KW - SARS-CoV-2/genetics

UR - https://www.scopus.com/pages/publications/105029508245

U2 - 10.1038/s41588-025-02484-9

DO - 10.1038/s41588-025-02484-9

M3 - Journal article

C2 - 41571831

AN - SCOPUS:105029508245

SN - 1061-4036

VL - 58

SP - 299

EP - 306

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

Abstract

Keywords

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