Dataset Information

Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation.

ABSTRACT: Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, we report a multivariate genome-wide association studies of 23 immunoglobulin G (IgG) N-glycosylation phenotypes. In the discovery cohort, our multi-phenotype method uncovers ten genome-wide significant loci, of which five are novel (IGH, ELL2, HLA-B-C, AZI1, FUT6-FUT3). We convincingly replicate all novel loci via multivariate tests. We show that IgG N-glycosylation loci are strongly enriched for genes expressed in the immune system, in particular antibody-producing cells and B lymphocytes. We empirically demonstrate the efficacy of multivariate methods to discover novel, reproducible pleiotropic effects.Multivariate analysis methods can uncover the relationship between phenotypic measures characterised by modern omic techniques. Here the authors conduct a multivariate GWAS on IgG N-glycosylation phenotypes and identify 5 novel loci enriched in immune system genes.

SUBMITTER: Shen X

PROVIDER: S-EPMC5587582 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation.

Shen Xia X Klarić Lucija L Sharapov Sodbo S Mangino Massimo M Ning Zheng Z Wu Di D Trbojević-Akmačić Irena I Pučić-Baković Maja M Rudan Igor I Polašek Ozren O Hayward Caroline C Spector Timothy D TD Wilson James F JF Lauc Gordan G Aulchenko Yurii S YS

Nature communications 20170906 1

Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, we report a multivariate genome-wide association studies of 23 immunoglobulin G (IgG) N-glycosylation phenotypes. In the discovery cohort, our multi-ph ...[more]

PMID: 28878392

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Project description:Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27 × 10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.

Project description:Abstract Background Schizophrenia is a highly heritable psychiatric disorder. In the past 30 years, thousands of case-control and family-designed association studies have examined candidate genes for schizophrenia. To assist the field in interpreting this large volume of gene-association studies, the online SzGene database was created and included meta analyses for 287 polymorphisms at the time of its final update in 2010. However, since then more than one-thousand new gene-association studies in schizophrenia have been conducted. As such, we have conducted an updated systematic review and meta-analysis of all gene-association studies in schizophrenia published before March 2017. Methods Studies published between January 2010 and March 2017 were identified using a customized querying strategy. Identified gene-association studies were included in the review and meta-analysis if they: 1) were case-control or family-designed studies with polymorphisms detected in schizophrenia or schizoaffective patients, 2) provide sufficient data to perform meta-analysis, and 3) were not genome-wide association studies (GWAS). Random-effects meta-analysis was performed on polymorphisms with four or more independent studies. Results Raw data of 1711 studies included in the SzGene database were integrated with 1368 studies identified from our systematic literature search. Random-effects meta-analysis were applied to 540 polymorphisms with at least four studies and 89 of these polymorphisms were nominally associated with SZ (unadjusted p < 0.05). After bonferroni correction, 12 polymorphisms remained statistically significant, including five associations not reported in the most recent Psychiatric Genomics Consortium schizophrenia GWAS: 1) rs11098403, p = 1.45e-10, odds ratio = 0.65; 2) rs12807809, p = 7.04e-06, odds ratio = 0.91; 3) rs910694 in PDE4B: p = 1.05e-05, odds ratio = 0.77; 4) rs1801133 in MTHFR: p = 2.99e-05, odds ratio = 1.13 and 5) rs1602565: p = 7.73e-05, odds ratio = 1.11. Discussion Our results provide a comprehensive and up-to-date review of candidate gene association studies in schizophrenia. Findings complement results from GWASs in schizophrenia but also expand the current list of candidate loci for schizophrenia.

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Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation.

Publications

Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation.

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