Bidirectional Causal Associations Between Plasma Metabolites and Parkinson's Disease

In plasma samples of patients with neuropsychitraic disorders, the levels of many metabolites differ from those in healthy controls. Causal connections between Parkinson's disease (PD), one of the most prevalent degenerative disorders, and the levels of plasma metabolites remain unclear. Bidirectional metabolome-wide Mendelian randomization (MR) analysis was performed to explore the potential causative associations between PD in a genome-wide association study (GWAS) dataset with 5,150 cases and 448,583 controls, and the levels of 871 plasma circulating metabolites (N = 8,299). The MR analysis detected 38 metabolites associated with PD. Fourteen of these metabolites were associated with a reduced risk of PD (odds ratio (OR): 0.86-0.92), along with 24 metabolites contributing to elevated risks of PD (OR: 1.06-1.23). In reverse MR analysis, genetic signature of PD had positive causal effects on the levels of 35 circulating metabolites (OR: 1.04-1.07) and negative causal effects on the levels of 13 metabolites (OR: 0.94-0.96). For three circulating metabolites levels, including behenoyl dihydrosphingomyelin (d18:0/22:0), 1-stearoyl-GPE (18:0) as well as N-palmitoyl-sphingadienine (d18:2/16:0), bi-directional causative relationships with PD were uncovered. Our findings revealed a network of bidirectional causal associations between the levels of individual plasma metabolites and the risks of PD, providing possible clues for the prevention and the therapy of this disorder.