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The Parkinson's Disease Mendelian Randomization Research Portal.

ABSTRACT: BACKGROUND:Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE:To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS:We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS:We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS:We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Noyce AJ

PROVIDER: S-EPMC6973052 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The Parkinson's Disease Mendelian Randomization Research Portal.

Noyce Alastair J AJ Bandres-Ciga Sara S Kim Jonggeol J Heilbron Karl K Kia Demis D Hemani Gibran G Xue Angli A Lawlor Debbie A DA Smith George Davey GD Duran Raquel R Gan-Or Ziv Z Blauwendraat Cornelis C Gibbs J Raphael JR Hinds David A DA Yang Jian J Visscher Peter P Cuzick Jack J Morris Huw H Hardy John J Wood Nicholas W NW Nalls Mike A MA Singleton Andrew B AB

Movement disorders : official journal of the Movement Disorder Society 20191028 12

<h4>Background</h4>Mendelian randomization is a method for exploring observational associations to find evidence of causality.<h4>Objective</h4>To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research.<h4>Methods</h4>We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures ...[more]

PMID: 31659794

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Project description:BackgroundParkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.MethodsThis study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.ResultsElevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).ConclusionThis genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.

Project description:BackgroundPrevious epidemiological studies have reported an association between Sjögren's syndrome (SS) and Parkinson's disease (PD); however, the causality and direction of this relationship remain unclear. In this study, we aimed to investigate the causal relationship between genetically determined SS and the risk of PD using bidirectional Mendelian randomization (MR).MethodsSummary statistics for Sjögren's syndrome used as exposure were obtained from the FinnGen database, comprising 1,290 cases and 213,145 controls. The outcome dataset for PD was derived from the United Kingdom Biobank database, including 6,998 cases and 415,466 controls. Various MR methods, such as inverse variance weighted (IVW), Mendelian randomization Egger regression (MR-Egger), weighted median (WM), simple mode, weighted mode, MR-pleiotropy residual sum and outlier (MR-PRESSO), and robust adjusted profile score (RAPS), were employed to investigate the causal effects of SS on PD. Instrumental variable strength evaluation and sensitivity analyses were conducted to ensure the reliability of the results. In addition, reverse MR analysis was performed to examine the causal effects of PD on SS.ResultsThe WM, IVW, RAPS and MR-PRESSO methods demonstrated a significant association between genetically predicted SS and reduced risk of PD (odds ratio ORWM = 0.9988, ORIVW = 0.9987, ORRAPS = 0.9987, ORMR-PRESSO = 0.9987, respectively, P < 0.05). None of the MR analyses showed evidence of horizontal pleiotropy (P > 0.05) based on the MR-Egger and MR-PRESSO tests, and there was no statistical heterogeneity in the test results of the MR-Egger and IVW methods. The leave-one-out sensitivity analysis confirmed the robustness of the causal relationship between SS and PD. Furthermore, reverse MR analysis did not support any causal effects of PD on SS.ConclusionOur MR study supports a potential causal association between SS and a reduced risk of PD. Further extensive clinical investigations and comprehensive fundamental research are warranted to elucidate the underlying mechanisms linking SS and PD.

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The Parkinson's Disease Mendelian Randomization Research Portal.

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