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Abdominal multi-organ iron content and the risk of Parkinson's disease: a Mendelian randomization study
Mingrui Yang1, Cheng Tang1, Fei Peng1
1Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Background:
To evaluate the causal relationship between abdominal multi-organ iron content and PD risk using publicly available genome-wide association study (GWAS) data.
Methods:
We conducted MR analysis to assess the effects of iron content in various abdominal organs on PD risk, followed by reverse analysis. Additionally, MVMR analysis evaluated the independent effects of organ-specific iron content on PD. We utilized genetic variation data from the UK Biobank, including liver iron content (n = 32,858), spleen iron content (n = 35,324), and pancreas iron content (n = 25,617), as well as summary-level data for Parkinson's disease from the FinnGen (n = 218,473) and two other large GWAS datasets of European populations (First dataset n = 480,018; Second dataset n = 2,829). The primary MR analysis used the inverse variance-weighted (IVW) method, confirmed by MR-Egger and weighted median methods. Sensitivity analysis was performed to address potential pleiotropy and heterogeneity. Observational cohort results were validated through replication cohort analysis, followed by meta-analysis.
Results:
IVW analysis revealed a causal relationship between increased liver iron content and elevated risk of PD (OR = 1.27; 95% CI: 1.05-1.53; p = 0.015). No significant causal relationship was observed between spleen (OR = 1.00; 95% CI: 0.76-1.32; p = 0.983) and pancreatic (OR = 0.93; 95% CI: 0.72-1.20; p = 0.573) iron content and increased risk of PD. Meta-analysis of GWAS data for PD from three different sources using the random-effects IVW method showed a statistically significant causal relationship between liver iron content and the occurrence of PD (OR = 1.17, 95% CI: 1.01-1.35; p = 0.012).
Conclusion:
This study presents evidence from Mendelian randomization (MR) analysis indicating a significant causal link between increased liver iron content and a higher risk of Parkinson's disease (PD). These findings suggest that interventions targeting body iron metabolism, particularly liver iron levels, may be effective in preventing PD.
Insights
Increased liver iron content is causally linked to a higher risk of Parkinson's disease (PD). Targeting iron metabolism, especially in the liver, may help prevent PD.
Area of Science:
- Genetics
- Neurology
- Metabolism
Background:
- Iron accumulation in abdominal organs has been hypothesized to influence Parkinson's disease (PD) risk.
- Understanding the specific organ contributions to PD pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the potential causal relationship between iron content in the liver, spleen, and pancreas and the risk of developing Parkinson's disease.
- To utilize Mendelian randomization (MR) analysis with large-scale genome-wide association study (GWAS) data for robust causal inference.
Main Methods:
- Mendelian randomization (MR) analysis was performed using genetic variants associated with iron levels in the liver, spleen, and pancreas.
- Inverse variance-weighted (IVW) method was the primary analysis, with MR-Egger and weighted median methods used for sensitivity analyses.
- Multivariable MR (MVMR) assessed independent effects, and meta-analysis combined results from multiple large GWAS datasets for Parkinson's disease.
Main Results:
- A significant causal effect was found between higher liver iron content and an increased risk of Parkinson's disease (OR=1.27, p=0.015).
- No significant causal relationship was observed between spleen or pancreatic iron content and Parkinson's disease risk.
- Meta-analysis confirmed the association between elevated liver iron and PD occurrence (OR=1.17, p=0.012).
Conclusions:
- This study provides strong evidence for a causal link between increased liver iron content and higher Parkinson's disease risk.
- Findings suggest that modulating liver iron levels could be a potential therapeutic strategy for Parkinson's disease prevention.
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