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


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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.

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Biomarkers, Databases, Genetic, Genetic Variation, Humans, Mendelian Randomization Analysis, Parkinson Disease, Polymorphism, Single Nucleotide, Uric Acid
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Annals of Neurology
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Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
DAK is supported by an MB PhD Award from the International Journal of Experimental Pathology. AJN is funded by Parkinson’s UK (ref G1606) and the Barts Charity (Preventive Neurology Unit). GDS and DAL work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_1201/1 and MC_UU_1201/5). DAL is a National Institute of Health Research Senior Investigator (NF-SI-0166-10196). MN, AS and AN participation in this study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH. University College London Hospitals and University College London receive support from the Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres (BRC). NWW is an NIHR senior Investigator and receives support from the JPND-MRC COmprehensive Unbiased Risk factor Assessment for Genetics and Environment in Parkinson’s disease (COURAGE).