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

ABSTRACT: Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.

SUBMITTER: Sharapov SZ

PROVIDER: S-EPMC6664388 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Sharapov Sodbo Zh SZ Tsepilov Yakov A YA Klaric Lucija L Mangino Massimo M Thareja Gaurav G Shadrina Alexandra S AS Simurina Mirna M Dagostino Concetta C Dmitrieva Julia J Vilaj Marija M Vuckovic Frano F Pavic Tamara T Stambuk Jerko J Stambuk Jerko J Trbojevic-Akmacic Irena I Kristic Jasminka J Simunovic Jelena J Momcilovic Ana A Campbell Harry H Doherty Margaret M Dunlop Malcolm G MG Farrington Susan M SM Pucic-Bakovic Maja M Gieger Christian C Allegri Massimo M Louis Edouard E Georges Michel M Suhre Karsten K Spector Tim T Williams Frances M K FMK Lauc Gordan G Aulchenko Yurii S YS

Human molecular genetics 20190601 12

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured ...[more]

PMID: 31163085

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Project description:The current disease model for leishmaniasis suggests that only a proportion of infected individuals develop clinical disease, while others are asymptomatically infected due to immune control of infection. The factors that determine whether individuals progress to clinical disease following Leishmania infection are unclear, although previous studies suggest a role for host genetics. Our hypothesis was that canine leishmaniasis is a complex disease with multiple loci responsible for the progression of the disease from Leishmania infection.Genome-wide association and genomic selection approaches were applied to a population-based case-control dataset of 219 dogs from a single breed (Boxer) genotyped for ~170,000 SNPs. Firstly, we aimed to identify individual disease loci; secondly, we quantified the genetic component of the observed phenotypic variance; and thirdly, we tested whether genome-wide SNP data could accurately predict the disease.We estimated that a substantial proportion of the genome is affecting the trait and that its heritability could be as high as 60%. Using the genome-wide association approach, the strongest associations were on chromosomes 1, 4 and 20, although none of these were statistically significant at a genome-wide level and after correcting for genetic stratification and lifestyle. Amongst these associations, chromosome 4: 61.2-76.9 Mb maps to a locus that has previously been associated with host susceptibility to human and murine leishmaniasis, and genomic selection estimated markers in this region to have the greatest effect on the phenotype. We therefore propose these regions as candidates for replication studies. An important finding of this study was the significant predictive value from using the genomic information. We found that the phenotype could be predicted with an accuracy of ~0.29 in new samples and that the affection status was correctly predicted in 60% of dogs, significantly higher than expected by chance, and with satisfactory sensitivity-specificity values (AUC = 0.63).

Dataset Information

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

Publications

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

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