[en] The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.
Disciplines :
Genetics & genetic processes
Author, co-author :
Shadrina, Alexandra S; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia
Zlobin, Alexander ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics ; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia
Zaytseva, Olga O; Genos Glycoscience Research Laboratory, Zagreb 10000, Croatia
Klarić, Lucija; Genos Glycoscience Research Laboratory, Zagreb 10000, Croatia ; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Sharapov, Sodbo Z; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia
D Pakhomov, Eugene; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia
Perola, Marcus; Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare (THL), Helsinki, Finland
Esko, Tonu; Estonian Genome Center, University of Tartu, Tartu, Estonia
Hayward, Caroline; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Wilson, James F; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK ; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh EH8 9AG, Scotland
Lauc, Gordan; Genos Glycoscience Research Laboratory, Zagreb 10000, Croatia
Aulchenko, Yurii S; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia ; PolyOmica, 's-Hertogenbosch 5237 PA, The Netherlands
Tsepilov, Yakov A; Laboratory of Glycogenomics, Institute of Cytology and Genetics, Novosibirsk 630090, Russia ; Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk 630090, Russia
MRC - Medical Research Council [GB] Ministry of Education and Science of the Russian Federation [RU] RSF - Russian Science Foundation [RU]
Funding text :
Russian Science Foundation (grant number 19-15-00115 to
A.S.Sh., S.Z.S., E.D.P and Y.S.A.); Ministry of Education and
Science of the RF via the Institute of Cytology and Genetics
(project 0259-2021-0009/AAAA-A17-117092070032-4 to A.S.Z.);
Russian Ministry of Science and Education under the 5-100
Excellence Programme (to Y.A.T.); RCUK Innovation Fellowship
from the National Productivity Investment Fund (MR/R026408/1
to L.K.); Croatian National Centre of Research Excellence in
Personalized Healthcare grant (#KK.01.1.1.01.0010 to O.O.Z. and
G.L.), Medical Research Council (UK) Quinquennial programme (to J.F.W.). The Viking Health Study—Shetland (VIKING) was
supported by the MRC Human Genetics Unit quinquennial
programme grant ‘QTL in Health and Disease’. DNA extractions
and genotyping were performed at the Edinburgh Clinical
Research Facility, University of Edinburgh. The CROATIA-Korcula
study was funded by grants from the Medical Research Council
(UK), and Republic of Croatia Ministry of Science, Education and
Sports research grants (108-1080315-0302). The SNP genotyping
for the CROATIA-Korcula2 cohort was performed in the core
genotyping laboratory of the Clinical Research Facility at the
Western General Hospital, Edinburgh, Scotland. The work of C.H.
was supported by an MRC University Unit Programme Grant
MC_UU_00007/10 (QTL in Health and Disease). The color figure
charges were funded by the Russian Science Foundation grant
number 19-15-00115.
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