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.
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