Replication of 10 novel loci involved in human plasma protein N-glycosylation using MALDI-MS and UHPLC-FD data

Timoshchuk, A.; Naber, A.; Slieker, R.; Soplenkova, A.; Maslov, D.; Potapova, N. A.; Nicolardi, S.; Elders, P. J. M.; Sijbrands, E. J. G.; Sharapov, S.; Hart, L. M. t.; Hoek, M. v.; Wuhrer, M.; Aulchenko, Y. S.

doi:10.1101/2025.08.01.668131

bioRxiv · 10.1101/2025.08.01.668131

Replication of 10 novel loci involved in human plasma protein N-glycosylation using MALDI-MS and UHPLC-FD data

Timoshchuk, A.·Naber, A.·Slieker, R.·Soplenkova, A.·Maslov, D.·Potapova, N. A.·Nicolardi, S.·Elders, P. J. M.·Sijbrands, E. J. G.·Sharapov, S.·Hart, L. M. t.·Hoek, M. v.·Wuhrer, M.·Aulchenko, Y. S.

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Abstract

N-glycans are essential components of glycoproteins, influencing their properties and functions. While biochemical pathways of glycosylation are well-characterized, their genetic regulation remains poorly understood. This study utilizes matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) and ultra-high performance liquid chromatography-fluorescence detection (UHPLC-FD) to strengthen replication and further characterize previously identified genome-wide association signals for the total human plasma N-glycome (TPNG). Univariate and multivariate genetic association meta-analyses involved 3,385 samples across 143 N-glycome traits from the Hoorn Diabetes Care System and DiaGene cohorts as well as 3,224 samples across 117 N-glycome traits from TwinsUK, CEDAR, QMDiab and SABRE cohorts. We successfully replicated ten previously identified but not replicated glycosylation quantitative trait loci (glyQTLs) and prioritized five high-confidence putative causal genes, including the glycosyltransferase MGAT4B and inflammation-related genes - C3 and FCGR2B. The linkage-specific sialic acid derivatization in MALDI-MS enabled delineation of genetic effects on 2,3- and 2,6-sialylation. Mass spectrometry analysis also provided evidence for glucuronic acid-containing glycans in human blood plasma. These findings advance our understanding of the genetic regulation of protein N-glycosylation and highlight the complementarity of different analytical approaches in glycomics research.

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Timoshchuk, A., Naber, A., Slieker, R., Soplenkova, A., Maslov, D., Potapova, N. A., Nicolardi, S., Elders, P. J. M., Sijbrands, E. J. G., Sharapov, S., Hart, L. M. t., Hoek, M. v., Wuhrer, M., Aulchenko, Y. S.. 2025-08-03. Replication of 10 novel loci involved in human plasma protein N-glycosylation using MALDI-MS and UHPLC-FD data. https://doi.org/10.1101/2025.08.01.668131

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