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Publications

Journal Article Preprint Epublish

PubMed: 39606378 DOI: 10.1101/2024.11.21.24317689

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

medRxiv

Authors: Frank Geller, Xiaoping Wu, Vilma Lammi, Erik Abner, Jesse Tyler Valliere, Katerina Nastou, Morten Rasmussen, Niklas Worm Andersson, 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, 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

Affiliations

  • Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
  • Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Molecular and Population Genetics Program, Broad Institute, Cambridge, MA, USA.
  • Virus Research and Development Laboratory, Virus & Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark.
  • Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
  • Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.
  • Department of Obstetrics and Gynecology, Copenhagen University Hospital, Amager & Hvidovre Hospital, Copenhagen, Denmark.
  • Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Department of Nephrology and Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Danish National Biobank, Statens Serum Institut, Copenhagen, Denmark.
  • Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
  • Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
  • Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
  • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
  • Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Viro-Immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Statens Serum Institut, Copenhagen, Denmark.
  • Pharmacovigilance Research Center, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Abstract

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.

MeSH

Genes, Sars-Cov-2, Blood, Genetic Predisposition To Disease, Genome, Covid-19, Severe Acute Respiratory Syndrome-Related Coronavirus, Infections