TY - JOUR
T1 - The genetics and epidemiology of N- and O-immunoglobulin A glycomics
AU - Visconti, Alessia
AU - Rossi, Niccolò
AU - Bondt, Albert
AU - Ederveen, Agnes Hipgrave
AU - Thareja, Gaurav
AU - Koeleman, Carolien A M
AU - Stephan, Nisha
AU - Halama, Anna
AU - Lomax-Browne, Hannah J
AU - Pickering, Matthew C
AU - Zhou, Xu-Jie
AU - Wuhrer, Manfred
AU - Suhre, Karsten
AU - Falchi, Mario
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/8/9
Y1 - 2024/8/9
N2 - BACKGROUND: Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.METHODS: We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.RESULTS: We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.CONCLUSIONS: Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
AB - BACKGROUND: Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.METHODS: We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.RESULTS: We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.CONCLUSIONS: Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
KW - Humans
KW - Glycomics
KW - Immunoglobulin A/blood
KW - Glycosylation
KW - Genome-Wide Association Study
KW - Female
KW - Male
KW - Polysaccharides/metabolism
KW - Adult
KW - Immunoglobulin G/blood
KW - Middle Aged
KW - Aged
UR - http://www.scopus.com/inward/record.url?scp=85200896831&partnerID=8YFLogxK
U2 - 10.1186/s13073-024-01369-6
DO - 10.1186/s13073-024-01369-6
M3 - Article
C2 - 39123268
SN - 1756-994X
VL - 16
SP - 96
JO - Genome medicine
JF - Genome medicine
IS - 1
M1 - 96
ER -