Author Identifiers

Xingang Li
ORCID: 0000-0003-0252-154X

Date of Award

2020

Degree Type

Thesis

Degree Name

Doctor of Philosophy

School

School of Medical and Health Sciences

First Advisor

Professor Wei Wang

Second Advisor

Associate Professor Peter Roberts

Third Advisor

Dr Manshu Song

Abstract

Genome-wide association studies (GWAS) have identified over 60 genetic loci associated with IgG N-glycosylation; however, the causal genes and their abundance in relevant tissues are uncertain. In this study, firstly, I leveraged data from GWAS summary statistics for 8,090 Europeans, and large-scale expression quantitative trait loci (eQTL) data from the genotype-tissue expression of 53 types of tissues (GTEx v7), to derive a linkage disequilibrium score for the specific expression of genes (LDSC-SEG) and conduct a transcriptome-wide association study (TWAS). I identified 55 genes whose predicted levels of expression were significantly associated with IgG Nglycosylation in 14 tissues with regard to three working scenarios, i.e., tissue-specific, pleiotropic and co-associated, for candidate genetic predisposition affecting IgG N-glycosylation traits. Secondly, through pathway enrichment, I defined 23 of 55 candidate genes being enriched in several IgG N-glycosylation-related pathways, such as asparagine N-linked glycosylation, Nglycan biosynthesis and transport to the Golgi and subsequent modification. Thirdly, through phenome-wide association studies (PheWAS), I found most genetic variants underlying TWAS hits being correlated with health measures (height, waist-hip ratio, systolic blood pressure) and diseases, such as systemic lupus erythematosus, inflammatory bowel disease and Parkinson’s disease, which are related to IgG N-glycosylation. This study provides an atlas of genetic regulatory loci and their target genes within functionally relevant tissues, for further studies on the mechanisms of IgG N-glycosylation and its related diseases.

Available for download on Thursday, January 18, 2024

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