Investigating the causality of metabolites involved in one-carbon metabolism with the risk and age at onset of Parkinson's disease: a two-sample mendelian randomization study

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterised by the progressive degeneration of dopaminergic (DA) neurons. The cause of degeneration is not well understood; however, both genetics and environmental factors, such as nutrition, have been implicated in the disease process. Deficiencies in one-carbon metabolism in particular have been associated with increased risk for PD onset and progression, though the precise relationship is unclear. The aim of the present review is to determine the role of one-carbon metabolism and elevated levels of homocysteine in PD onset and pathology and to identify potential mechanisms involved. A search of PubMed, Google Scholar and Web of Science was undertaken to identify relevant human and animal studies. Case–control, prospective cohort studies, meta-analyses and non-randomised trials were included in the present review. The results from human studies indicate that polymorphisms in one-carbon metabolism may increase risk for PD development. There is an unclear role for dietary B-vitamin intake on PD onset and progression. However, dietary supplementation with B-vitamins may be beneficial for PD-affected individuals, particularly those on l-DOPA (levodopa or l-3,4-dihydroxyphenylalanine) treatment. Additionally, one-carbon metabolism generates methyl groups, and methylation capacity in PD-affected individuals is reduced. This reduced capacity has an impact on expression of disease-specific genes that may be involved in PD progression. During B-vitamin deficiency, animal studies report increased vulnerability of DA cells through increased oxidative stress and altered methylation. Nutrition, especially folates and related B-vitamins, may contribute to the onset and progression of PD by making the brain more vulnerable to damage; however, further investigation is required.

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Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Nature Communications ◽

10.1038/s41467-021-26280-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Catherine S. Storm ◽

Demis A. Kia ◽

Mona M. Almramhi ◽

Sara Bandres-Ciga ◽

Chris Finan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drug Targets ◽

Molecular Mechanisms ◽

Mendelian Randomization ◽

Disease Risk ◽

Target Identification ◽

Causal Effect ◽

Age At Onset ◽

Drug Repurposing

AbstractParkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

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Predicting the efficacy of exenatide in Parkinson’s disease using genetics – a Mendelian randomization study

10.1101/2020.10.20.20215855 ◽

2020 ◽

Author(s):

Catherine S. Storm ◽

Demis A. Kia ◽

Mona Almramhi ◽

Dilan Athauda ◽

Stephen Burgess ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Type 2 Diabetes Mellitus ◽

Brain Tissue ◽

Mendelian Randomization ◽

Disease Risk ◽

Age At Onset

AbstractBackgroundExenatide is a glucagon-like peptide 1 receptor (GLP1R) agonist used in type 2 diabetes mellitus that has shown promise for Parkinson’s disease in a phase II clinical trial. Drugs with genetic evidence are more likely to be successful in clinical trials. In this study we investigated whether the genetic technique Mendelian randomization (MR) can “rediscover” the effects of exenatide on diabetes and weight, and predict its efficacy for Parkinson’s disease.MethodsWe used genetic variants associated with increased expression of GLP1R in blood to proxy exenatide, as well as variants associated with expression of DPP4, TLR4 and 15 genes thought to act downstream of GLP1R or mimicking alternative actions of GLP-1 in blood and brain tissue. Using an MR approach, we predict the effect of exenatide on type 2 diabetes risk, body mass index (BMI), Parkinson’s disease risk and several Parkinson’s disease progression markers.ResultsWe found that genetically-raised GLP1R expression in blood was associated with lower BMI and possibly type 2 diabetes mellitus risk, but not Parkinson’s disease risk, age at onset or progression. Reduced DPP4 expression in brain tissue was significantly associated with increased Parkinson’s disease risk.ConclusionsWe demonstrate the usefulness of MR using expression data in predicting the efficacy of a drug and exploring its mechanism of action. Our data suggest that GLP-1 mimetics like exenatide, if ultimately proven to be effective in Parkinson’s disease, will be through a mechanism that is independent of GLP1R in blood.

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Effect of plasma vitamin C levels on Parkinson’s disease and age at onset: a Mendelian randomization study

Journal of Translational Medicine ◽

10.1186/s12967-021-02892-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Haijie Liu ◽

Yan Zhang ◽

Haihua Zhang ◽

Longcai Wang ◽

Tao Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Vitamin C ◽

Large Scale ◽

Mendelian Randomization ◽

Age At Onset ◽

Causal Link ◽

Plasma Vitamin ◽

Causal Association ◽

Weighted Median

Abstract Background Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. Methods We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. Results We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: [− 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: [− 3.396, − 0.105], P = 0.037) and MR-Egger (beta = − 2.592, 95% CI: [− 4.623, − 0.560], P = 0.012). Conclusions We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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A voxel-based PET study of dopamine transporters in Parkinson's disease: Relevance of age at onset

Neurobiology of Disease ◽

10.1016/j.nbd.2008.03.012 ◽

2008 ◽

Vol 31 (1) ◽

pp. 102-109 ◽

Cited By ~ 21

Author(s):

Andrea Panzacchi ◽

Rosa Maria Moresco ◽

Valentina Garibotto ◽

Angelo Antonini ◽

Clara Gobbo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Age At Onset ◽

Dopamine Transporters ◽

Disease Relevance

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Parkinson’s Disease and Ischemic Stroke: a Bidirectional Mendelian Randomization Study

Translational Stroke Research ◽

10.1007/s12975-021-00974-6 ◽

2022 ◽

Author(s):

Shiyuan Fang ◽

Xinzhi Hu ◽

Tao Wang ◽

Yutong Yang ◽

Ran Xu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Ischemic Stroke ◽

Mendelian Randomization

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Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.679568 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bin Li ◽

Guihu Zhao ◽

Qiao Zhou ◽

Yali Xie ◽

Zheng Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Association Studies ◽

Age At Onset ◽

Genetic Data ◽

Genome Wide Association Studies ◽

Onset Age ◽

Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

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FAKTOR-FAKTOR YANG MEMPENGARUHI SUBTIPE GEJALA MOTORIK PENYAKIT PARKINSON

Human Care Journal ◽

10.32883/hcj.v5i1.649 ◽

2020 ◽

Vol 5 (1) ◽

pp. 343

Author(s):

Attiya Istarini ◽

Yuliarni Syafrita ◽

Restu Susanti

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Age At Onset ◽

Motor Symptom ◽

Disease Stage ◽

Motor Symptoms ◽

Research Subjects ◽

Cross Sectional ◽

Duration Of Disease ◽

Cross Sectional Design

Background: Parkinson's disease (PD) is a chronic neurodegenerative disease that manifests as movement disorders. Based on motor symptoms, PD is classified into subtypes of tremor and postural instability gait disorders (PIGD). The motor symptoms subtype is a predictor of disease progression, therapeutic response, and quality of life for Parkinson's patients. The purpose of this study is to identify some factors that influence motor symptoms in Parkinson's disease.Methods: This research use cross sectional design. Samples were selected by consecutive sampling method that met the inclusion and exclusion criteria. Research subjects were 58 people. Statistical analysis using SPSS. p values <0.05 were considered statistically significant.Results: This research include 58 patients, 55.2% were men with range of age 63.5 ± 8.5 years old. The mean age at onset was 57.9 ± 9.5 years and duration of disease 6.1 ± 4.6 years. Motor symptoms 53.4% dominant tremor. There was a significant relationship between disease stage and motor symptom subtypes (p <0.001). There is no relationship between the patient's age, age at onset and duration of the disease with motor symptom subtypes.Conclusions: There is a relationship between disease stage and motor symptom. The patient's age, age at onset and duration of the disease are not related to the motor symptoms of Parkinson's patients.

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