Heritability Enrichment of Immunoglobulin G N-Glycosylation in Specific Tissues

Genome-wide association studies (GWAS) have identified over 60 genetic loci associated with immunoglobulin G (IgG) N-glycosylation; however, the causal genes and their abundance in relevant tissues are uncertain. Leveraging 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), we derived a linkage disequilibrium score for the specific expression of genes (LDSC-SEG) and conducted a transcriptome-wide association study (TWAS). We identified 55 gene associations whose predicted levels of expression were significantly associated with IgG N-glycosylation in 14 tissues. Three working scenarios, i.e., tissue-specific, pleiotropic, and coassociated, were observed for candidate genetic predisposition affecting IgG N-glycosylation traits. Furthermore, pathway enrichment showed several IgG N-glycosylation-related pathways, such as asparagine N-linked glycosylation, N-glycan biosynthesis and transport to the Golgi and subsequent modification. Through phenome-wide association studies (PheWAS), most genetic variants underlying TWAS hits were found to be 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. Our 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.