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

Abstract

There is increasing evidence on inflammation as a determinant in the pathogenesis of Parkinson’s disease. But, its role in parkinsonian neurodegeneration remains elusive: it´s not clear if inflammatory cascades are causes or consequences of dopamine neurons death. In the present study, we aim at performing 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 to date genome-wide association studies (sample size ranging from 13,955 to 204,402 individuals) conducted on European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist, and tumor 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 findings’ consistency. In all the three data sources selected for interleukin-6, we found statistical evidence for earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration (years difference per 1 log-unit increase = -2.364, 95% CI = -4.789 to 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 tumor 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.

Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease

“…We also found IL-6 rs1800795 G>C decreased the PD risk, which may lower the level of IL-6 in serum (163). A MR analysis study also demonstrated that the pro-inflammatory activity of the IL-6 could be a determinant of prodromal PD (35).…”

“…Mendelian Randomization (MR) is a reliable genetic epidemiology method, which uses genetic variants as instrumental variable (IV) to assure whether causality exists between exposure and outcome, maybe a powerful tool to explore the causality between inflammation and PD (34). Bottigliengo D et al investigated the causal role of inflammation on PD by conducting MR analysis (35). They included C-reactive protein (CRP), IL-6, IL-1 receptor antagonist and TNF-a in a two-sample MR analysis and suggested the pro-inflammatory activity of IL-6 could be a determinant of prodromal PD.…”

Mitochondrial dysfunction underlies cortical atrophy in prodromal synucleinopathies

“…A recent investigation confirmed this sequence of events, showing that pro-inflammatory cytokines are a causal factor of prodromal PD and that an earlier age at onset of PD is associated with increased interleukin-6 concentration. 52 In addition, we found that greater surface area in iRBD occurred in regions with a greater expression of genes involved in metal detoxification processes. This is in line with a study that combined quantitative susceptibility mapping and imaging transcriptomics and identified that the regions showing the greatest iron deposition in PD were those with a greater expression of genes involved in metal detoxification.…”

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

“…Previous MR studies on Alzheimer's disease 10,12,[25][26][27][28][29][30][31][32][33] suggest potential causal associations with BIN1, CCL27, C3, CD33, CD4 T cells, GDF-15 and SVEP1, whereas MR studies on Parkinson's disease suggest a potential causal association with GPNMB, IL-6 and MIP1b. Compared with these studies, we used a stricter P value cutoff with multiple testing correction and were able to replicate associations between BIN1, CD33 and Alzheimer's disease and those between GPNMB and Parkinson's disease.…”

“…To our knowledge, this is the most comprehensive MR and triangulation study to date on immune system-and BBB-related biomarkers as risk factors of dementia-causing diseases. Our MR focused on 1,827 biomarkers whereas earlier MR analyses included fewer than 200 biomarkers specific to these systems 10,12,[25][26][27][28][29][30][31][32][33] . We obtained the strongest causal evidence for autoimmunity-and inflammation-related AZGP1 (ref.…”