scholarly journals Unhealthy Behaviours and Risk of Parkinson’s Disease: A Mendelian Randomisation Study

2021 ◽  
pp. 1-13
Author(s):  
Karl Heilbron ◽  
Melanie P. Jensen ◽  
Sara Bandres-Ciga ◽  
Pierre Fontanillas ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protective Effect ◽  
Tobacco Smoking ◽  
Alcohol Intake ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Split Sample ◽  
The Impact

Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921–0.991; p = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025–1.235; p = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979–0.997; p = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

scholarly journals Unhealthy Behaviours and Parkinson’s Disease: A Mendelian Randomisation Study

2020 ◽  
Author(s):  
Karl Heilbron ◽  
Melanie P. Jensen ◽  
Sara Bandres-Ciga ◽  
Pierre Fontanillas ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protective Effect ◽  
Tobacco Smoking ◽  
Alcohol Intake ◽  
Mendelian Randomisation ◽  
Increased Risk ◽  
Split Sample ◽  
Reduced Risk ◽  
High Bmi

AbstractObjectiveTobacco smoking, alcohol intake, and high BMI have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD). Because of the possibility of residual confounding and reverse causation, it is unclear whether such epidemiological associations are causal. Mendelian randomisation (MR) uses genetic variants to explore causal effects of exposures on outcomes; minimising these sources of bias. Using MR, this study sought to determine the causal relationship between tobacco smoking, alcohol intake, and high BMI, and the risk of PD.MethodsWe performed genome-wide association studies to identify single nucleotide polymorphisms associated with the exposures. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. The inverse variance weighted (IVW) method was used to combine SNP-specific effect estimates.ResultsEver-smoking causally reduced risk of PD (OR 0.955; 95% confidence interval [CI] 0.921-0.991; p=0.013). An increase in daily alcohol intake causally increased risk of PD (OR 1.125, 95% CI 1.025-1.235; p=0.013) and a 1 kg/m2 BMI causally reduced risk of PD (OR 0.988, 95% CI 0.979-0.997; p=0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments.InterpretationUsing split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD, warranting the prioritisation of related therapeutic targets, such as nicotinic agonists, in prevention trials. In contrast to observational data, alcohol consumption causally increased risk of PD. Higher BMI had a protective effect on PD, but the effect was small.

scholarly journals Rheumatoid arthritis decreases risk for Parkinson’s disease: a Mendelian randomization study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
ChunYu Li ◽  
RuWei Ou ◽  
HuiFang Shang
Keyword(s):  
Rheumatoid Arthritis ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Correlation ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Standard Deviation Increase ◽  
Rheumatoid Arthritis Risk

AbstractEpidemiological and clinical studies have suggested comorbidity between rheumatoid arthritis and Parkinson’s disease (PD), but whether there exists a causal association and the effect direction of rheumatoid arthritis on PD is controversial and elusive. To evaluate the causal relationship, we first estimated the genetic correlation between rheumatoid arthritis and PD, and then performed a two-sample Mendelian randomization analysis based on summary statistics from large genome-wide association studies of rheumatoid arthritis (N = 47,580) and PD (N = 482,703). We identified negative and significant correlation between rheumatoid arthritis and PD (genetic correlation: −0.10, P = 0.0033). Meanwhile, one standard deviation increase in rheumatoid arthritis risk was associated with a lower risk of PD (OR: 0.904, 95% CI: 0.866–0.943, P: 2.95E–06). The result was robust under all sensitivity analyses. Our results provide evidence supporting a protective role of rheumatoid arthritis on PD. A deeper understanding of the inflammation and immune response is likely to elucidate the potential pathogenesis of PD and identify therapeutic targets for PD.

scholarly journals The Parkinson’s Disease Mendelian Randomization Research Portal

2019 ◽  
Author(s):  
Alastair J Noyce ◽  
Sara Bandres-Ciga ◽  
Jonggeol Kim ◽  
Karl Heilbron ◽  
Demis Kia ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
P Value ◽  
Phenotypic Traits ◽  
Genome Wide Association Studies ◽  
Summary Statistics

ABSTRACTBackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.ObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson’s disease (PD) in a large, unbiased manner, and to create a public resource for research.MethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.ResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.DiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

scholarly journals Genome‐wide association studies of LRRK2 modifiers of Parkinson's disease

2021 ◽  
Author(s):  
Dongbing Lai ◽  
Babak Alipanahi ◽  
Pierre Fontanillas ◽  
Tae‐Hwi Schwantes‐An ◽  
Jan Aasly ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

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

Genes ◽  
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.

scholarly journals Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo

2020 ◽  
Author(s):  
Melissa Conti Mazza ◽  
Victoria Nguyen ◽  
Alexandra Beilina ◽  
Jinhui Ding ◽  
Mark R. Cookson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Association Studies ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Genome Wide Association Studies ◽  
Double Knockout ◽  
Knockout Mouse Model

AbstractCoding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

scholarly journals Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

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 &gt; 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.

The role of α-synuclein in neurodegeneration — An update

2012 ◽  
Vol 3 (2) ◽  
Author(s):  
Kurt Jellinger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Bound States ◽  
Physiological Function ◽  
Neuronal Degeneration ◽  
Association Studies ◽  
Common Mechanism ◽  
Genome Wide Association Studies ◽  
Potential Biomarker

AbstractGenetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson’s disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson’s disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

Gene Co-Expression Network Analysis Implicates microRNA Processing in Parkinson’s Disease Pathogenesis

2018 ◽  
Vol 18 (4) ◽  
pp. 191-199 ◽  
Author(s):  
Jason A. Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Network Analysis ◽  
Statistical Power ◽  
Association Studies ◽  
Model Systems ◽  
Specific Cell ◽  
Genome Wide Association Studies ◽  
Microrna Processing ◽  
Highly Correlated

Background: Recent advances in genetics have provided insights into important inherited causes of Parkinson’s disease (PD), but the underlying biological mechanisms are still incompletely understood. Gene expression studies have pointed toward the dysregulation of neuroinflammation, mitochondrial function, and protein degradation pathways. Objective: We aimed to identify groups of dysregulated genes in PD. Methods: In order to increase statistical power and control for potential confounders, we re-analyzed transcriptomic data from PD patients and model systems, integrating additional genomic data using a systems biology approach. Using weighted gene co-expression network analysis, we partitioned genes into co-expressed modules. Results: One co-expression module, M13, had an expression trajectory that was highly correlated with PD, was not characterized by any specific cell type markers, and was enriched in PD genes identified by genome-wide association studies. Genes within M13 seemed to be related to global microRNA biogenesis, and DICER1 and AGO3 were highly connected within the module. The NUCKS1 gene, previously identified as part of the PARK16 locus, was also a hub gene within M13. Conclusion: These results suggest that microRNA processing and function may play a role in the pathogenesis of PD, and thus may represent a useful target for future drug development.

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