A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.

There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson's disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson's disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson's disease (28 568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = -2.364, 95% confidence interval (CI) = -4.789-0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

Bottigliengo D ，Foco L ，Seibler P ，Klein C ，König IR ，Del Greco M F ... -  《-》

Inflammation and heart failure: a two-sample Mendelian randomization study.

It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach. Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method. We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias. This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias.

Remmelzwaal S ，van Oort S ，Handoko ML ，van Empel V ，Heymans SRB ，Beulens JWJ ... -  《-》

Sleep behaviors and Parkinson's disease: A bidirectional Mendelian randomization analysis.

Whether the quantity and quality of sleep are the risk factors for the development of Parkinson's disease remains unclear though it has now been confirmed that the quality of sleep among patients with Parkinson's disease is affected at the prodromal and clinical stages. Accordingly, this study aimed to examine the bidirectional causal relationships of multiple sleep-related phenotypes with Parkinson's disease using a two-sample Mendelian randomization (MR) method. The summary-level data collected from the published genome-wide association studies was used for analysis. Besides, the genetic relationships between different sleep-related phenotypes, including self-reported and accelerometer measured traits, were estimated for the risk and age at the onset of Parkinson's disease. To conduct MR analysis, inverse variance weighted, weight median, MR-Egger, and MR-PRESSO method were mainly used. Moreover, sensitivity analyses were carried out to examine the pleiotropic effect. In general, there was insufficient evidence to support the causal effect of sleep-related phenotypes on risk (N cases/controls = 33,674/449,056) and age at the onset (N cases = 28,568) of Parkinson's disease. However, the results of this study indicated that the later onset age of Parkinson's disease was related to the frequent occurrence of insomnia (OR [95% CI] 1.007 [1.003, 1.011], P < 0.001) after the adjustment for multiple testing. The results of this study suggest that insomnia-associated single nucleotide polymorphisms are more frequent in later onset Parkinson's disease patients compared to earlier onset patients. However, given the limitations of statistical power and potential bias, further validation should be still conducted through larger population research.

Ling Y ，Zhu J ，Yan F ，Tse LA ，Kinra S ，Jiang M ... -  《-》

The Parkinson's Disease Mendelian Randomization Research Portal.

Mendelian randomization is a method for exploring observational associations to find evidence of causality. 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. 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. 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. 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.

Noyce AJ ，Bandres-Ciga S ，Kim J ，Heilbron K ，Kia D ，Hemani G ，Xue A ，Lawlor DA ，Smith GD ，Duran R ，Gan-Or Z ，Blauwendraat C ，Gibbs JR ，23andMe Research Team5, International Parkinson's Disease Genomics Consortium (IPDGC) ，Hinds DA ，Yang J ，Visscher P ，Cuzick J ，Morris H ，Hardy J ，Wood NW ，Nalls MA ，Singleton AB ... -  《-》

Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study.

Hartwig FP ，Borges MC ，Horta BL ，Bowden J ，Davey Smith G ... -  《-》