Mendelian randomization: investigating causal relationship between urate and Parkinson's disease

Abstract

Objective: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson’s Disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk. Methods: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study dataset which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median based (PWM) approach, were used to assess potential bias due to pleiotropy or invalid instruments. Results: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of OR 1.03 (95% CI 0.88–1.20) per 1 SD increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR 0.99 [95% CI 0.83-1.17] and 0.99 [95% CI 0.86−1.14], respectively). Interpretation: We do not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be in part due to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk.