Assessment Of Causal Factors For Parkinson'S Disease In European Populations: A Phenome-Wide Mendelian Randomisation Analysis

Background and Objectives: To assess the causality of potentially modifiable factors, including lifestyle, nutrients, lipids, anthropometric traits, and inflammatory factors of Parkinson's disease (PD), genetic instruments for modifiable factors were identified from genome-wide association studies (GWAS). Methods and Study Design: Genetic associations for PD (1,239 cases and 451,025 matched controls) were extracted from the UK Biobank GWAS summary statistics. The causal effects of modifiable factors on the risk of PD were estimated using the multiplicative random-effects inverse variance weighted method (IVW). Results: In the IVW analysis, a decreased risk for PD was causally associated with genetically predicted smoking cessation (odds ratio 0.41, [95% confidence interval] 0.32-0.78; p<0.001), and higher bone mineral density (0.43, 0.38 -0.71; p<0.001), higher concentrations of vitamin B-12 (0.56, 0.43-0.91; p<0.001), docosahexenoic acid (0.52, 0.37-0.71; p<0.001), and sIL-6R (0.69, 0.58-0.75; p<0.001). Instead, analysis further supported the role of apolipoprotein (a) isoform size(1.67, 1.36-1.71; p<0.001), being a genetically morning person (2.18, 1.12-4.72; p<0.001), and number of cigarette smoking (1.05, 1.01-1.08; p<0.001) in contributing to the risk of developing PD. Conclusions: Our findings provide new evidence for the potential positive causal association of cigarette smoking number and apolipoprotein (a) isoform size and the inverse causal association of vitamin B-12, docosahexaenoic acid, smoking cessation, and soluble interleukin-6 receptor with PD, which contributes to the development of new interventions for PD.