Defining the genetic control of human blood plasma N-glycome using genome-wide association study

Abstract

45Glycosylation is a common post-translational modification of proteins. It is known, that glycans 46 are directly involved in the pathophysiology of every major disease. Defining genetic factors 47 altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical 48 applications. Here, we report a genome-wide association study of the human blood plasma N-49 glycome composition in up to 3811 people. We discovered and replicated twelve loci. This 50 allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG 51 glycosylation. Majority of loci contained genes that encode enzymes directly involved in 52 glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and 53 MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of 54 plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which 55 potentially highlights the role of glycoprotein degradation pathway, and such transcription factor 56 as IKZF1. 57 58 59Glycosylation -addition of carbohydrates to a substrate -is a common cotranslational and 60 posttranslational modification of proteins. that affects the physical properties of proteins 61 (solubility, conformation, folding, stability, trafficking, etc.) [1-4] as well as their biological 62 functions -from protein-protein interactions, interaction of proteins with receptors, to cell-cell, 63 cell-matrix, and host-pathogen interactions [2,3,5,6]. It has been estimated that more than half of 64 all proteins are glycosylated [7][8][9]. Given the fact that glycans participate in many biological 65 processes, it is therefore not surprising that molecular defects in protein glycosylation pathways 66 are increasingly recognized as direct causes of diseases, such as rheumatoid arthritis, 67 cardiometabolic disorders, cancer, variety of autoimmune diseases, type 2 diabetes, inflammatory 68 bowel disease and others [10][11][12][13][14][15][16][17]. More specifically, a variety of N-glycan structures are now 69 considered as disease markers and represent diagnostic as well as therapeutic targets [5,12,[18][19][20][21][22][23][24][25]. 70Defining the genetic control of protein glycosylation expands our knowledge about the regulation 71 of this fundamental biological process, and it may also shed new light onto how alterations in 72 glycosylation can lead to the development of complex human diseases [11]. 73

Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease

“…Further, given the effect of alternative N-glycosylation at the Asn297 site in the Fc domain of IgG on antibody effector function ( 37 ) and the initial observations of hypogalactosylation associated with ZIP8 391-Thr ( 19 , 21 ), we hypothesized that there would be an association between ZIP8 391-Thr and N-glycosylation of IgG. To study associations between ZIP8 391-Thr and the N-glycome, we used GWAS of human blood plasma ( n = 2763) ( 38 ) and IgG N-glycome ( n = 8080) ( 39 ), where N-glycome profiles were analyzed using ultra-high-performance liquid chromatography (UHPLC). The frequency of ZIP8 391-Thr was 8% and 8.3%, respectively; notably, ZIP8 391-Thr (rs13107325) was not included in the initial analyses, as it was not included on the original genotyping arrays.…”

“…To explore the association between ZIP8 391-Thr and human N-glycome in human population-based samples, we used the results of recently published GWAS of human blood plasma N-glycome ( n = 2763) ( http://doi.org/10.5281/zenodo.1298406 ) ( 38 ) and IgG N-glycome ( n = 8080) ( https://datashare.is.ed.ac.uk/handle/10283/3238 ) ( 39 ), where N-glycome profiles were analyzed using UHPLC. We performed a single-SNP glycome-wide association analysis among 113 total plasma N-glycome traits and 77 IgG N-glycome traits using publicly available GWAS summary statistics.…”

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

“…To further validate our findings, we analyzed all significantly associated SNPs in a cohort where glycans were measured with liquid chromatography coupled to electrospray mass spectrometry (LCMS; N = 1842). From the 27 genome-wide significant SNPs, 17 were associated with at least one of the LCMS-measured IgG glycopeptide levels at Bonferroni-corrected P ≤ 3.7 × 10 −5 . Of these 17, 14 loci were also replicated in the UPLC replication study (table S2).…”

“…None of the randomly selected SNPs exhibited such a strong correlation with these two loci in the permutation analysis ( Table 2 and table S6). Recent work by Sharapov et al (17) on genetics of the total plasma proteome N-glycosylation, of which IgG is a major part, suggested that the likely candidate gene is DERL3. DERL3 encodes a protein involved in endoplasmic reticulum-associated degradation for misfolded luminal glycoproteins.…”

Correcting for sparsity and non-independence in glycomic data through a systems biology framework

“…Previous work has investigated the similarity across glycans using glycan motifs, such as, glycan fingerprinting to describe glycan diversity in databases 17 , align glycan structures 18 , identify glycan epitopes in glycoprofiles 19 , deconvolve LC-MS data to clarify glycan abundance 20 , or compare glycans in glycoprofiles leveraging simple structures 21 . These tools use information on glycan composition or epitopes; however, further accounting for shared biosynthetic steps across glycans could provide complete biosynthetic context to all glycan epitopes.…”