TY - JOUR

T1 - A genome-wide association study of the plasma N-glycome of 10,000 individuals significantly expands the list of associated loci

AU - Шарапов, Содбо Жамбалович

AU - Timoshchuk, Anna N.

AU - Зайцева, Ольга Олеговна

AU - Maslov, Denis

AU - Soplenkova, Anna

AU - Елгаева, Елизавета Евгеньевна

AU - Vuckovic, Frano

AU - Trbojević-Akmačić, Irena

AU - Williams, Frances M.K.

AU - Primorac, Dragan

AU - Zundert, Jan van

AU - Georges, Michel

AU - Suhre, Karsten

AU - Allegri, Massimo

AU - Chaturvedi, Nishi

AU - Dunlop, Malcolm G.

AU - Schulze, Matthias Bernd

AU - Spector, Timothy D.

AU - Цепилов, Яков Александрович

AU - Lauc, Gordan

AU - Аульченко, Юрий Сергеевич

N1 - Conference code: 57

PY - 2024

Y1 - 2024

N2 - Background/Objectives: Glycosylation is a post-translational protein modification that impacts their physico-chemical properties as well as biological functions. While the biochemical pathways of glycosylation are well studied, its genetic regulation remains incompletely understood. Here we aimed to identify and replicate new loci associated with blood plasma N-glycosylation, propose novel genes that regulate N-glycosylation, and explore the potential role of N-glycans in the control of complex traits and multifactorial diseases.Methods: We performed univariate and multivariate genome-wide association meta-analyses on more than 10,000 individuals, examining 117 N-glycome traits. To identify causal genes for each replicated locus, we used eight in silico-based predictors. We performed a bidirectional mendelian randomization to identify potential causal relationships between glycans and diseases.Results: We identified 16 novel loci and prioritized 13 novel genes contributing to N-glycosylation. Among these were glycosyltransferase gene ABO, as well as other genes associated with lipid metabolism – GCKR, FADS2, TRIB1, and GRAMD1B, which, to our knowledge, is the first time lipid metabolism and its regulation has been linked to the human blood plasma protein N-glycosylation. We found causal relationships between high-mannose glycans, asthma, and lipoprotein metabolism disorders.Conclusion: By integrating glycomics, proteomics, transcriptomics, and genomics, we provide a resource that facilitates deeper exploration of disease pathogenesis and supports drug discovery and development efforts.Grants: This work was partially supported by the Research Program at the MSU Institute for Artificial Intelligence. The study was conducted using the UK Biobankresource under application #59345.Conflict of Interest: Sodbo Sharapov: None declared, Anna Timoshchuk: None declared, Olga Zaytseva: None declared, Denis Maslov: None declared, Anna Soplenkova: None declared, Elizaveta Elgaeva: None declared, Frano Vuckovic: None declared, Irena Trbojević-Akmačić: None declared, Frances Williams: None declared, Dragan Primorac: None declared, Jan van Zundert: None declared, Michel Georges: None declared, Karsten Suhre: None declared, Massimo Allegri: None declared, Nish Chaturvedi: None declared, Malcolm Dunlop: None declared, Matthias Bernd Schulze: None declared, Tim Spector: None declared, Yakov Tsepilov: None declared, Gordan Lauc G.L. is the founder and owner of Genos Glycoscience Research Laboratory,a private research organization that specializes in high-throughput glycomicanalysis and has several patents in this field., Yury Aulchenko Employee of GSK

AB - Background/Objectives: Glycosylation is a post-translational protein modification that impacts their physico-chemical properties as well as biological functions. While the biochemical pathways of glycosylation are well studied, its genetic regulation remains incompletely understood. Here we aimed to identify and replicate new loci associated with blood plasma N-glycosylation, propose novel genes that regulate N-glycosylation, and explore the potential role of N-glycans in the control of complex traits and multifactorial diseases.Methods: We performed univariate and multivariate genome-wide association meta-analyses on more than 10,000 individuals, examining 117 N-glycome traits. To identify causal genes for each replicated locus, we used eight in silico-based predictors. We performed a bidirectional mendelian randomization to identify potential causal relationships between glycans and diseases.Results: We identified 16 novel loci and prioritized 13 novel genes contributing to N-glycosylation. Among these were glycosyltransferase gene ABO, as well as other genes associated with lipid metabolism – GCKR, FADS2, TRIB1, and GRAMD1B, which, to our knowledge, is the first time lipid metabolism and its regulation has been linked to the human blood plasma protein N-glycosylation. We found causal relationships between high-mannose glycans, asthma, and lipoprotein metabolism disorders.Conclusion: By integrating glycomics, proteomics, transcriptomics, and genomics, we provide a resource that facilitates deeper exploration of disease pathogenesis and supports drug discovery and development efforts.Grants: This work was partially supported by the Research Program at the MSU Institute for Artificial Intelligence. The study was conducted using the UK Biobankresource under application #59345.Conflict of Interest: Sodbo Sharapov: None declared, Anna Timoshchuk: None declared, Olga Zaytseva: None declared, Denis Maslov: None declared, Anna Soplenkova: None declared, Elizaveta Elgaeva: None declared, Frano Vuckovic: None declared, Irena Trbojević-Akmačić: None declared, Frances Williams: None declared, Dragan Primorac: None declared, Jan van Zundert: None declared, Michel Georges: None declared, Karsten Suhre: None declared, Massimo Allegri: None declared, Nish Chaturvedi: None declared, Malcolm Dunlop: None declared, Matthias Bernd Schulze: None declared, Tim Spector: None declared, Yakov Tsepilov: None declared, Gordan Lauc G.L. is the founder and owner of Genos Glycoscience Research Laboratory,a private research organization that specializes in high-throughput glycomicanalysis and has several patents in this field., Yury Aulchenko Employee of GSK

UR - https://www.nature.com/articles/s41431-024-01733-5

M3 - Conference article

VL - 32

SP - 1177

EP - 1178

JO - European journal of human genetics

JF - European journal of human genetics

SN - 1018-4813

IS - S2

M1 - EP17.012

T2 - 57th European Society of Human Genetics Conference

Y2 - 1 June 2024 through 4 June 2024

ER -