Comprehensive mendelian randomization analysis of human plasma proteome to identify potential drug targets for essential tremor

We performed a systematic causal analysis of the plasma proteome, to discover potential protein markers and therapeutic targets for essential tremor (ET). Protein quantitative trait loci (pQTLs) of 4853 plasma proteins were derived from 7 published genome-wide association studies of the plasma proteome. A 2-sample Mendelian randomization (MR) study was conducted to assess the potential causal relationships between 4853 plasma proteins and ET. Summary-data-based MR and Bayesian colocalization analyses were performed to confirm the causal roles of the candidate proteins. Phenome-wide-MR (Phe-MR) was used to assess the selected potential side effects. Two-sample MR and Summary-data-based MR predicted that 6 targets were associated with ET: antioxidant 1 copper chaperone (ATOX1), carbonic anhydrase 3, carbonyl reductase 3 (CBR3), glycoprotein NMB (GPNMB), hyaluronan binding protein 4 (HABP4), and LARGE xylosyl- and glucuronyltransferase (LARGE). Further colocalization analyses indicated that ATOX1, HABP4 and LARGE were colocalized with ET. Furthermore, Phe-MR revealed no potential side effects associated with the candidate proteins. Our comprehensive analysis indicates a causal relationship between genetically determined levels of ATOX1, HABP4, and LARGE and the risk of ET. The identified proteins may serve as promising protein markers and drug targets for ET. Additional investigations are necessary to investigate the functions of these potential proteins in ET.