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.

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

2020 ◽  
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Mendelian Randomization ◽  
Association Studies ◽  
Conclusive Evidence ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genetic Liability ◽  
Genome Wide ◽  
Relationship Of

Latest evidence revealed a possible association between Parkinson’s disease (PD) and periodontitis. We explored the causal relationship of this 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 PD and periodontitis. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Eight non-overlapping SNPs of periodontitis from an additional GWAS assisted in the validation of association being studied. 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 found no association of genetically primed PD towards periodontitis (B= -0.0001, SE 0.0001, P = 0.19). This MR study found no conclusive evidence to support a bidirectional causal genetic liability between PD and periodontitis. Further GWAS studies are needed to confirm the consistency of these results.

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 Diet‐Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1 Million People

2021 ◽  
Author(s):  
Leon G. Martens ◽  
Jiao Luo ◽  
Ko Willems van Dijk ◽  
J. Wouter Jukema ◽  
Raymond Noordam ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Lower Risk ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Blood Levels ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Blood Concentrations ◽  
Vitamins E And C

Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, β‐carotene, and retinol), which were assessed as either absolute blood levels and/or high‐throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome‐wide association studies ( P <5×10 −8 ). We used summary statistics for single‐nucleotide polymorphisms–stroke associations from 3 European‐ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance–weighted analyses and subsequently meta‐analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85–1.05) for vitamin C and 1.04 (95% CI, 0.99–1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98–1.03) for retinol and 1.12 (95% CI, 0.88–1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary‐derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.

scholarly journals Establishing gene regulatory networks from Parkinson's disease risk loci

2021 ◽  
Author(s):  
Sophie L Farrow ◽  
William Schierding ◽  
Sreemol Gokuladhas ◽  
Evgeniia Golovina ◽  
Tayaza M. Fadason ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Association Studies ◽  
Adult Brain ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Gene Regulatory

The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent single nucleotide polymorphisms (SNPs) across 78 genomic regions associated with Parkinson's disease (PD), yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with PD-SNPs, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 PD-SNPs across 49 tissues, that encompass 36 peripheral and 13 CNS tissues. Notably, one third of these genes were regulated via trans- acting mechanisms (distal; risk locus-gene separated by > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and PD GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of PD. Through utilising Louvain clustering we extracted nine significant and highly intra-connected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with PD. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of PD-SNPs, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of PD.

scholarly journals PARK16 rs708730 polymorphism decreases Parkinson’s disease risk in European ancestry population: a meta-analysis

2020 ◽  
Vol 1 (2) ◽  
Author(s):  
Zhijie Han ◽  
Baochu Wei ◽  
Chenghong Zhang ◽  
Hongtian Zhu ◽  
Lei Tang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protective Factor ◽  
Association Studies ◽  
Minor Allele ◽  
European Ancestry ◽  
Small Scale ◽  
Genome Wide Association Studies ◽  
Allele Variant ◽  
Different Populations

Parkinson’s disease (PD) is a complex fatal chronic neurodegenerative disease most common in elderly people. The early genome-wide association studies (GWAS) found that the minor allele variant of PARK16 rs708730 polymorphism is a significant protective factor for PD in Caucasian populations. However, these results cannot be repeated by the following studies in Caucasian populations and other populations. We considered that the inconsistency of the findings may be caused by the small-scale samples or the heterogeneity among different populations. Therefore, in this study, we synthesized the previous related GWAS studies through three authoritative sources, and used the large-scale samples (10,645 PD cases and 30,499 controls) to reevaluate the association between rs708730 polymorphism and PD. The results showed that there is no association between them in Asian ancestry population. While, in European ancestry population, we found that the minor allele variant (G) of rs708730 polymorphism is significantly associated with a decreased risk of PD. Collectively, our findings further verified the association of rs708730 with PD and show its genetic heterogeneity among different populations, which can help to develop a better understanding of the PD’s pathogenesis.

scholarly journals Parkinson’s Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes

2020 ◽  
Author(s):  
Alix Booms ◽  
Steven E. Pierce ◽  
Gerhard A. Coetzee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Cell Type ◽  
Genome Wide ◽  
Risk Snps ◽  
A Cell ◽  
Regulatory Dna

AbstractGenome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinson’s disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 ‘SNPs of interest’ from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at the SLC50A1, SNCA, BAG3, FBXL19, SETD1A, and NUCKS1 loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for PD.

Reference SVA insertion polymorphisms are associated with dopaminergic degeneration in Parkinson’s Disease and differential gene expression in the PPMI cohort

2020 ◽  
Author(s):  
Abigail L Pfaff ◽  
Vivien J. Bubb ◽  
John P. Quinn ◽  
Sulev Koks
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Differential Gene Expression ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sequencing Data ◽  
Genome Wide ◽  
Differential Gene

Abstract Background: The development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. The majority of studies investigating the genetic component of complex diseases, including PD, have focused on single nucleotide polymorphisms as this enables genome wide analysis of a large number of samples. Genome wide association studies have been crucial in identifying PD risk variants, however a large proportion of the heritability of PD remains to be identified. To investigate the component of PD that may involve complex genetic variants we characterised SINE-VNTR-Alus (SVAs), a retrotransposon known to affect gene expression, in the Parkinson’s Progression Markers Initiative (PPMI) cohort.Results: Utilising whole genome sequencing from the PPMI cohort that consisted of 179 healthy controls, 371 individuals with PD and 58 individuals classified as SWEDD (scans without evidence of dopaminergic deficit) we genotyped SVAs in the reference genome for their presence or absence identifying 81 such SVAs. Seven of these SVAs were associated with progression of the disease, including four whose specific genotypes were linked to an increase in the gradient of dopaminergic loss when comparing the caudate to putamen from DaTscan imaging analysis. These seven SVAs also demonstrated regulatory properties as they were associated with differential gene expression in whole blood RNA sequencing data.Conclusion: This study highlights the importance of addressing variation of SVAs and potentially other types of retrotransposons in PD genetics, furthermore these SVA elements should be considered as regulatory domains that could play a role in disease progression.

scholarly journals Diversity in Parkinson’s disease genetics research: current landscape and future directions

2021 ◽  
Author(s):  
Artur F. Schumacher-Schuh ◽  
Andrei Bieger ◽  
Olaitan Okunoye ◽  
Kin Mok ◽  
Shen-Yang Lim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Population Diversity ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetics Research ◽  
Genome Wide ◽  
A Genome ◽  
The Future

AbstractHuman genetics research lacks diversity; over 80% of genome-wide association studies (GWAS) have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. This systematic review provides an overview of research involving Parkinson’s disease (PD) genetics in under-represented populations (URP), and sets a baseline to measure the future impact of current efforts in those populations.We searched PubMed and EMBASE until October 2021 using search strings for “PD”, “genetics”, the main “URP”, and “lower-to-upper-middle-income countries”. Inclusion criteria were original studies, written in English, reporting genetic results on PD patients from non-European populations. Two levels of independent reviewers identified and extracted relevant information.We observed considerable imbalances in PD genetic studies among URP. Asian participants from China were described in the majority of the articles published (61%), but other populations were less well studied, for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just seven studies using a genome-wide approach published up to 2021 including URP.This review provides insight into the significant lack of population diversity in PD research highlighting the urgent need for better representation. The Global Parkinson’s Genetics Program (GP2) and similar initiatives aim to impact research in URP, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future.

scholarly journals Causal Association Between Periodontitis and Type 2 Diabetes: A Bidirectional Two-Sample Mendelian Randomization Analysis

2022 ◽  
Vol 12 ◽  
Author(s):  
Yong-Bo Wang ◽  
Si-Yu Yan ◽  
Xu-Hui Li ◽  
Qiao Huang ◽  
Li-Sha Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Bidirectional Association

Background: Previous observational studies have reported a bidirectional association between periodontitis and type 2 diabetes, but the causality of these relationships remains unestablished. We clarified the bidirectional causal association through two-sample Mendelian randomization (MR).Methods: We obtained summary-level data for periodontitis and type 2 diabetes from several published large-scale genome-wide association studies (GWAS) of individuals of European ancestry. For the casual effect of periodontitis on type 2 diabetes, we used five independent single-nucleotide polymorphisms (SNPs) specific to periodontitis from three GWAS. The summary statistics for the associations of exposure-related SNPs with type 2 diabetes were drawn from the GWAS in the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) consortium and the FinnGen consortium R5 release, respectively. For the reversed causal inference, 132 and 49 SNPs associated with type 2 diabetes from the DIAGRAM consortium and the FinnGen consortium R5 release were included, and the summary-level statistics were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium. Multiple approaches of MR were carried out.Results: Periodontitis was not causally related with the risk of type 2 diabetes (all p &gt; 0.05). No causal effect of type 2 diabetes on periodontitis was found (all p &gt; 0.05). Estimates were consistent across multiple MR analyses.Conclusion: This study based on genetic data does not support a bidirectional causal association between periodontitis and type 2 diabetes.

scholarly journals Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

2020 ◽  
Author(s):  
M. Ryan Corces ◽  
Anna Shcherbina ◽  
Soumya Kundu ◽  
Michael J. Gloudemans ◽  
Laure Frésard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Association Studies ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Chromatin Accessibility ◽  
Adult Brain ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms

ABSTRACTGenome-wide association studies (GWAS) have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the adult human brain through profiling of the chromatin accessibility landscapes and three-dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to integrate this multi-omic framework and predict dozens of functional single nucleotide polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for Alzheimer’s disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia and MAL in oligodendrocytes for Parkinson’s disease (PD). Moreover, we dissect the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene contacts in neurons that increase MAPT expression and may mediate this disease association. This work greatly expands our understanding of inherited variation in AD and PD and provides a roadmap for the epigenomic dissection of noncoding regulatory variation in disease.

Sign in / Sign up

Export Citation Format

Share Document