The genetics and epidemiology ofN-andO-IgA glycomics

Abstract

AbstractImmunoglobulin (Ig) glycosylation modulates the immune response, and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation. Here, we generated, using a novel LC-MS method, the first large-scale IgA glycomics dataset in serum from 2,423 twins, encompassing 71N-andO-glycan species. We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1,ELL2,B4GALT1,ABCF2,TMEM121,SLC38A10,SMARCB1,MGAT3), and two novel loci specifically modulating IgAO-glycosylation (C1GALT1andST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ethnicities. Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.