engleski

Genome-wide association meta-analysis reveals fourteen new loci associated with immunoglobulin G N-glycosylation

Glycosylation of the Fc-binding region of immunoglobulin G (IgG) is a highly complex biosynthetic process that involves a network of glycosyltransferase enzymes, co-factors, transporters, substrates and other components essential for glycan chain elongation and attachment. Previous GWAS efforts provided evidence for colocalization of IgG glycome- associated variants with variants affecting risk of inflammatory diseases, emphasizing the need for deeper understanding of genetic mechanisms involved in the regulation of the IgG glycosylation pathway. We conducted a genome-wide association meta- analysis by harmonizing IgG glycosylation data created by two different quantification platforms - LCMS (Liquid chromatography coupled with mass spectrometry) and UPLC (Ultra performance liquid chromatography), in seven cohorts of European descent (N=13705). The harmonised phenotypes were defined as percentage of presence of the given sugar moiety in the total IgG glycome. Association between 11 derived phenotypes and HRC-imputed genetic data was performed assuming an additive linear model. Meta- analysis was performed with METAL software using the fixed effect inverse- variance method. In the discovery analysis, we found 43 genome-wide significant loci (p ≤1x10-8), 28 of which replicate previous findings and 14 of which are novel. FUMA, a web-based platform, was used to perform functional mapping, followed by further annotation of variants using SIFT and Polyphen. A possibly damaging amino acid change was found in the SLC17A9 gene (rs7271712:Thr>Met) in a novel glycan association on chromosome 20. Colocalization of glycan-associated variants and blood eQTLs from the eQTLgen dataset was assessed using approximate Bayes factors from the coloc R- package. Shared causal variants between glycan levels and gene expression in blood were supported (posterior probability≥75%) for sixteen genes (COG7, DCTN5, NFKB1, ELL2, IL6ST, ANKRD55, KDELR2, MEF2B, IGHG2, EEF1A1, MTO1, KIF3C, MYCBP, KIF11, ACVR1C, TCF3), among which are genes that already have established roles in the immune system. Replication and further investigation of the loci are required but initial gene prioritization efforts point to immune system-related genes that potentially also have a role in IgG glycosylation.

IgG ; glycosylation ; GWAS

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