Dataset Information

Mendelian randomization study shows no causal relationship between circulating urate levels 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 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.

SUBMITTER: Kia DA

PROVIDER: S-EPMC6481555 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.

Kia Demis A DA Noyce Alastair J AJ White Jon J Speed Doug D Nicolas Aude A Burgess Stephen S Lawlor Debbie A DA Davey Smith George G Singleton Andrew A Nalls Mike A MA Sofat Reecha R Wood Nicholas W NW

Annals of neurology 20180801 2

<h4>Objective</h4>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.<h4>Methods</h4>We used a genetic instrument consisting of ...[more]

PMID: 30014513

Similar Datasets

Project description:BackgroundThis study aimed to evaluate the causal relationship between Interleukin-27 (IL-27) and osteoporosis by bidirectional Mendelian randomization (MR) analysis.MethodsFirstly, the genome-wide association study summary data of osteoporosis (finn-b-M13_OSTEOPOROSIS) and IL-27 levels (ebi-a-GCST90012017) were picked out from the Integrative Epidemiology Unit (IEU) OpenGWAS database. After filtrating instrumental variables (IVs), the bidirectional MR analysis between IL-27 levels and osteoporosis was performed by MR-Egger, Weighted median, Simple mode, Weighted mode, and Inverse variance weighted (IVW). Subsequently, the sensitivity analysis was adopted to evaluate the reliability of the MR results via the Heterogeneity, Horizontal pleiotropy test and Leave-One-Out (LOO) analysis. Finally, the enrichment analysis of genes corresponding to SNPs related to IL-27 levels derived from eQTLGen database was executed to explore in depth the biological function and regulatory mechanism of these genes on osteoporosis occurrence.ResultsThe bidirectional MR results based on IVW method revealed that IL-27 level as a risk factor was causally related to osteoporosis (P = 0.004, odds ratio (OR) = 1.123, 95% confidence interval (CI) = 1.037-1.217), whereas osteoporosis was not in significant connection with IL-27 levels (P > 0.05). In regard to the sensitivity analysis for forward MR results, there was no heterogeneity and horizontal pleiotropy, and no SNPs relevant to IL-27 levels existed severe bias, suggesting the reliability of forward MR analysis. Furthermore, a total of 74 genes corresponding to 26 SNPs of IL-27 levels were obtained and were mainly involved in immune and inflammatory pathways including MyD88-dependent toll-like receptor signaling pathway, Toll-like receptor signaling pathway, cytosolic DNA-sensing pathway and so forth.ConclusionsThis study supported that IL-27 level as a risk factor was causally connected with osteoporosis and might regulate the disease occurrence and progression by means of immune and inflammatory mechanisms, which could provide important reference and evidence for further exploring the role of IL-27 in the development of osteoporosis.

Project description:Parkinson's disease (PD) is a neurodegenerative disorder with extensive involvement of motor symptoms, imposing a heavy economic burden on patients and society. B lymphocytes, a group of immune cells associated with humoral immunity, have been shown to be involved in the pathogenesis of PD. However, the causal relationship and potential pathogenic effects of B cell in PD remain unclear. Based on the three core hypotheses of the Mendelian randomization (MR) study, we explored causal associations between 190 B-cell immunological traits and 482,730 European individuals (Ncase = 33,674, Ncontrol = 449,056) from genome wide association studies by means of the two-sample bidirectional MR method. The inverse‑variance weighted method was selected as the main approach when conducting MR analysis. Finally, the results were verified by the heterogeneity and horizontal pleiotropy analyses. Five B-cell immunological phenotypes were nominally associated with PD at the significance threshold of P < 0.05. Concretely, IgD + CD38- B cell %lymphocyte (OR 1.052, 95% CI 1.001-1.106, P = 0.046), CD20 on IgD- CD24- B cell (OR 1.060, 95% CI 1.005-1.117, P = 0.032), CD38 on IgD+ CD24- B cell (OR 1.113, 95% CI 1.028-1.206, P = 0.009), and BAFF-R on CD20- B cell (OR 1.093, 95% CI 1.010-1.184, P = 0.027) were identified as risk factors for PD. Instead, CD38 on Plasma Blast-Plasma Cell (OR 0.894, 95% CI 0.802-0.996, P = 0.043) was proved to be protective. However, there is no statistically significant correlation between B cell and PD after Bonferroni correction. The results of reverse MR were negative, avoiding the reverse causal effects. Eventually, the association results were identified as stable across several sensitivity analyses. Briefly, our study might demonstrate the key factor of B cells in PD. Further studies are warranted to clarify the associations for early identification and immunotherapeutic development in PD patients.

Dataset Information

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.

Publications

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets