[en] More than a half of plasma proteins are N-glycosylated. Most of them are synthesized, glycosylated, and secreted to the bloodstream by liver and lymphoid tissues. While associations with N-glycosylation are implicated in the rising number of liver, cardiometabolic, and immune diseases, little is known about the genetic regulation of this process. Here, we performed the largest genome-wide association study of N-glycosylation of the blood plasma proteome in 10,000 individuals. We doubled the number of genetic loci known to be associated with blood N-glycosylation by identifying 16 novel loci and prioritizing 13 novel genes contributing to N-glycosylation. Among these were the GCKR, TRIB1, HP, SERPINA1 and CFH genes. These genes are predominantly expressed in the liver and show a previously unknown genetic link between plasma protein N-glycosylation, metabolic and liver diseases, and inflammatory response. By integrating glycomics, proteomics, transcriptomics, and genomics, we provide a resource that facilitates deeper exploration of disease pathogenesis and supports the discovery of glycan-based biomarkers.
Disciplines :
Genetics & genetic processes
Author, co-author :
Sharapov, Sodbo ; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
Timoshchuk, Anna ; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
Zaytseva, Olga; Genos Glycoscience Research Laboratory, Borongajska cesta 83H, Zagreb, Croatia
Maslov, Denis E ; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
Soplenkova, Anna ; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
Elgaeva, Elizaveta E ; Institute of Cytology and Genetics, Novosibirsk, Russia ; Novosibirsk State University, Novosibirsk, Russia
Tiys, Evgeny S; Institute of Cytology and Genetics, Novosibirsk, Russia
Mangino, Massimo ; Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, St Thomas' Campus, Lambeth Palace Road, London, United Kingdom ; NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, United Kingdom
Wittenbecher, Clemens; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
Karssen, Lennart ; PolyOmica, 's-Hertogenbosch, Hertogenbosch, PA, The Netherlands
Timofeeva, Maria; Colon Cancer Genetics Group, Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom ; D-IAS, Danish Institute for Advanced Study, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9, Odense C, Denmark
Nostaeva, Arina ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale ; Institute of Cytology and Genetics, Novosibirsk, Russia ; PolyOmica, 's-Hertogenbosch, Hertogenbosch, PA, The Netherlands
Vuckovic, Frano ; Genos Glycoscience Research Laboratory, Borongajska cesta 83H, Zagreb, Croatia
Trbojević-Akmačić, Irena ; Genos Glycoscience Research Laboratory, Borongajska cesta 83H, Zagreb, Croatia
Štambuk, Tamara; Genos Glycoscience Research Laboratory, Borongajska cesta 83H, Zagreb, Croatia
Feoktistova, Sofya; Institute of Cytology and Genetics, Novosibirsk, Russia
Potapova, Nadezhda A; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Voroshilova, Viktoria; Institute of Cytology and Genetics, Novosibirsk, Russia ; Vavilov Institute of General Genetics Russian Academy of Sciences, Moscow, Russia
Williams, Frances ; Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, St Thomas' Campus, Lambeth Palace Road, London, United Kingdom
Primorac, Dragan ; St. Catherine Specialty Hospital, Ulica Kneza Branimira, 71E, Zagreb, Croatia ; University of Split School of Medicine, Split, Croatia ; University of Osijek School of Medicine, Osijek, Croatia
Van Zundert, Jan ; Department of Anesthesiology and Multidisciplinary Paincentre, ZOL, Genk, Lanaken, Belgium ; Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, P. Debyelaan 25, Maastricht, The Netherlands
Georges, Michel ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA)
Suhre, Karsten ; Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar
Allegri, Massimo ; Centre Lemanique d'antalgie et neuromodulation - EHC, Morges, Switzerland
Chaturvedi, Nishi ; MRC Unit for Lifelong Health & Ageing University College London, London, United Kingdom
Dunlop, Malcolm ; Colon Cancer Genetics Group, Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, Western General Hospital, The University of Edinburgh, Edinburgh, United Kingdom
Schulze, Matthias B ; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam- Rehbruecke, 14558, Nuthetal, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany ; Institute of Nutrition Science, University of Potsdam, Potsdam, Germany
Spector, Tim ; Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, St Thomas' Campus, Lambeth Palace Road, London, United Kingdom
Tsepilov, Yakov A ; Institute of Cytology and Genetics, Novosibirsk, Russia ; Wellcome Sanger Institute, Cambridge, United Kingdom
Lauc, Gordan ; Genos Glycoscience Research Laboratory, Borongajska cesta 83H, Zagreb, Croatia ; University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
Aulchenko, Yurii S ; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia. yurii@bionet.nsc.ru ; Institute of Cytology and Genetics, Novosibirsk, Russia. yurii@bionet.nsc.ru
The work of S.Sh., A.T., D.M., A.S., and Y.S.A. was supported by the Research Program at the Moscow State University (MSU) Institute for Artificial Intelligence. The study was conducted using the UK Biobank resource under application #59345. The work of E.E., Y.A.T. was supported by the budget project of the Institute of Cytology and Genetics FWNR-2022-0020. European Community\u2019s Seventh Framework Programme funded project PainOmics (602736). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. The TwinsUK Study was approved by London-Westminster Research Ethics Committee (REC reference EC04/015), and Guy\u2019s and St Thomas\u2019 NHS Foundation Trust Research and Development (R&D). The TwinsUK BioBank was approved by the HRA - Liverpool East Research Ethics Committee (REC reference 19/NW/0187), IRAS ID 258513. Glycan analysis performed in Genos was supported by Horizon Europe grants GlycanSwitch (ERC Synergy grant # 101071386), INITIALIZE (grant # 101094099) and SynHealth (grant #101159018). All participants provide written, informed consent. We thank Toma Keser, Mirna \u0160imurina, Marija Vilaj, Jerko \u0160tambuk, Ivan Gudelj, Thomas S. Klari\u0107, Jasminka Kri\u0161ti\u0107, Jelena \u0160imunovi\u0107, Julija Juri\u0107, Ana Mom\u010Dilovi\u0107, Najda Rudman, and Maja Hani\u0107 for their assistance with glycan analysis. We thank Dmitry Shtokalo for valuable discussion and the Federal Research Center for Information and Computational Technologies SB RAS (FRC ICT SB RAS) for assistance with computational resources.
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