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Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease
Author(s) -
Kia Demis A.,
Noyce Alastair J.,
White Jon,
Speed Doug,
Nicolas Aude,
Burgess Stephen,
Lawlor Debbie A.,
Davey Smith George,
Singleton Andrew,
Nalls Mike A.,
Sofat Reecha,
Wood Nicholas W.
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25294
Subject(s) - mendelian randomization , confounding , medicine , confidence interval , odds ratio , hyperuricemia , observational study , context (archaeology) , oncology , uric acid , genetics , biology , genotype , paleontology , genetic variants , gene
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 data set, 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 (PWM)‐based approach, were used to assess potential bias attributed 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 odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88–1.20) per 1‐standard‐deviation 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 did 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, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191–199