Related Experiment Video
Updated: Aug 13, 2025
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
Causal effect of gut-microbiota-derived metabolite trimethylamine N-oxide on Parkinson's disease: A Mendelian
Hang Zhou1, Yuqi Luo1, Wenjie Zhang1
1Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
Background And Purpose:
It has been suggested that trimethylamine N-oxide (TMAO) is related to Parkinson's disease (PD) in observational studies. However, the direction of this association is inconsistent. An exploratory Mendelian randomization study was conducted to investigate whether TMAO and its precursors have a causal relationship with PD.
Methods:
Summary statistics were obtained for single nucleotide polymorphisms related to circulating levels of TMAO, betaine, carnitine and choline, and the corresponding data for the risk, age at onset and progression of PD from genome-wide association studies. Inverse-variance weighting was used as the primary method for effect estimation. The false discovery rate was applied to the correction of multiple testing. A p value of association <0.05 but above the false discovery rate corrected threshold was deemed suggestive evidence of a possible association. A range of robust Mendelian randomization methods were used for sensitivity analysis.
Results:
Suggestive evidence was observed of an inverse causal effect of TMAO on motor fluctuations (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.731, 0.990, p = 0.037) and carnitine on insomnia (OR 0.817, 95% CI 0.700, 0.954, p = 0.010) and a positive causal effect of betaine on Hoehn-Yahr stage (OR 1.397, 95% CI 1.112, 1.756, p = 0.004), Unified Parkinson's Disease Rating Scale (UPDRS) III score (β = 0.138, 95% CI 0.051, 0.225, p = 0.002), motor fluctuations (OR 1.236, 95% CI 1.011, 1.511, p = 0.039), and choline on UPDRS IV (β = 0.106, 95% CI 0.026, 0.185, p = 0.009) and modified Schwab and England Activities of Daily Living Scale score (β = 0.806, 95% CI 0.127, 1.484, p = 0.020).
Conclusions:
Our findings provide suggestive evidence that TMAO and its precursors have a causal effect on the progression of PD. Further investigation of the underlying mechanisms is required.
Insights
Trimethylamine N-oxide (TMAO) and its precursors may causally influence Parkinson's disease (PD) progression. This Mendelian randomization study suggests potential links between these compounds and PD outcomes, warranting further investigation into underlying mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Metabolomics
Background:
- Observational studies suggest a link between trimethylamine N-oxide (TMAO) and Parkinson's disease (PD), but the association direction is unclear.
- Mendelian randomization (MR) is a powerful tool to infer causality using genetic variants as instrumental variables.
Purpose of the Study:
- To investigate the potential causal relationship between circulating levels of TMAO, betaine, carnitine, and choline, and the risk, onset, and progression of PD.
- To clarify the directionality of the association between TMAO and PD.
Main Methods:
- Utilized summary statistics from genome-wide association studies (GWAS) for TMAO, betaine, carnitine, choline, and PD outcomes.
- Employed inverse-variance weighting (IVW) as the primary MR analysis method.
- Applied false discovery rate (FDR) for multiple testing correction and conducted sensitivity analyses with various MR methods.
Main Results:
- Suggestive inverse causal effect of TMAO on motor fluctuations (OR 0.851) and carnitine on insomnia (OR 0.817).
- Suggestive positive causal effect of betaine on Hoehn-Yahr stage (OR 1.397), UPDRS III score (β=0.138), and motor fluctuations (OR 1.236).
- Suggestive positive causal effect of choline on UPDRS IV (β=0.106) and modified Schwab and England ADL score (β=0.806).
Conclusions:
- Findings provide suggestive evidence for a causal role of TMAO and its precursors in the progression of Parkinson's disease.
- Further research is needed to elucidate the specific mechanisms underlying these observed causal relationships.
Related Concept Videos
01:24Parkinson's Disease: Treatment
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
01:29Drugs Affecting Neurotransmitter Synthesis