Replication of fifteen loci involved in human plasma protein N-glycosylation in 4,802 samples from four cohorts

Sodbo Zh Sharapov, Alexandra S Shadrina, Yakov A Tsepilov, Elizaveta E Elgaeva, Evgeny S Tiys, Sofya G Feoktistova, Olga O Zaytseva, Frano Vuckovic, Rafael Cuadrat, Susanne Jäger, Clemens Wittenbecher, Lennart C Karssen, Maria Timofeeva, Therese Tillin, Irena Trbojević-Akmačić, Tamara Štambuk, Najda Rudman, Jasminka Krištić, Jelena Šimunović, Ana MomčilovićMarija Vilaj, Julija Jurić, Anita Slana, Ivan Gudelj, Thomas Klarić, Livia Puljak, Andrea Skelin, Antonia Jeličić Kadić, Jan Van Zundert, Nishi Chaturvedi, Harry Campbell, Malcolm Dunlop, Susan M Farrington, Margaret Doherty, Concetta Dagostino, Christian Gieger, Massimo Allegri, Frances Williams, Matthias B Schulze, Gordan Lauc, Yurii S Aulchenko

Research output: Contribution to journalArticlepeer-review

Abstract

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4,802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the sixteen loci reported previously, fifteen were replicated in our study. For the remaining locus (near the KREMEN1 gene) the replication power was low, and hence replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The fifteen replicated loci present a good target for further functional studies. Among these, eight genes encode glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4, and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.

Original languageEnglish
JournalGlycobiology
Early online date10 Jun 2020
DOIs
Publication statusE-pub ahead of print - 10 Jun 2020

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