Abstract
The pathophysiological mechanisms underlying type 2 diabetes mellitus (T2DM) remain incompletely understood, and the disease continues to impose a substantial burden on global health. In this study, we integrated the data from the largest genome-wide association study (GWAS; N = 898 130) of T2DM with human plasma protein quantitative trait locus (pQTL; N = 53 022) data to conduct the first proteome-wide association study (PWAS) of T2DM. Following Mendelian randomization and colocalization analyses, we identified 9 independent putatively causal proteins. Among these, 3 were successfully replicated in other independent pQTL datasets, including 2 (HYOU1 and FLT3) that were novel and not identified in the original GWAS. Further integration with expression quantitative trait locus (eQTL) data from 3 diabetes-related tissues (blood, adipose tissue, and pancreas) revealed that 5 of the causal proteins also showed significant associations with T2DM at their cis-regulatory mRNA levels. Subsequent functional annotation supported potential pathogenic roles of the causal proteins. Notably, drug repurposing analysis identified 29 candidate drugs for T2DM treatment by targeting 4 causal proteins. In conclusion, our findings provide new insights into the pathogenesis of T2DM and highlight promising targets for future mechanistic and therapeutic investigations.