Integrating plasma protein-centric multi-omics to evaluate the causal effect of glycosylation on the risk of cancer.

Glycosylation is a crucial post-translational modification, and numerous studies have reported its significant role in cancer progression. Nevertheless, no study has comprehensively analyzed the causal effect of glycosylation on the risk of cancer till now. Herein, we identified 32 SNPs of glycosylation-related genes (GRGs) that correlated with the risk of 8 kinds of cancer by summary-statistics-based mendelian randomization (SMR) analysis for genome-wide association study (GWAS) data. Next, the heterogeneity in dependent instrument (HEIDI) test and colocalisation analysis were utilized to verify the heterogeneity and consistency of SMR results. Further fine-mapping of causal gene set (FOCUS) analysis based on transcriptome-wide association study (TWAS) data showed that rs9810189 of ST6GAL1 and rs223489 of MANBA were negatively correlated with the risk of breast cancer and squamous cell carcinoma, respectively. Moreover, the MANBA protein in blood plasma also exhibited a probably negative causal effect on squamous cell carcinoma according to two-sample MR analyses for protein quantitative trait locus (pQTLs). In addition, single-cell RNA sequencing analysis and Kaplan-Meier plot analysis were performed to evaluate the potential role of GRGs in corresponding cancer prioritized by the above MR analysis. Finally, we attempted to illustrate the function of glycosyltransferases and investigate the druggable status of GRGs. Together, our study comprehensively analyzed the causal effect of glycosylation on cancer risk and identified potential strategies for cancer treatment.