scholarly journals LRRK2 coding variants and the risk of Parkinson’s disease

2021 ◽  
Author(s):  
Julie Lake ◽  
Xylena Reed ◽  
Rebekah G. Langston ◽  
Mike A. Nalls ◽  
Ziv Gan-Or ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Meta Analysis ◽  
European Ancestry ◽  
Allele Distribution ◽  
Gwas Signal ◽  
Lower Effect ◽  
Independent Association ◽  
Coding Variants

AbstractBackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinson’s disease risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinson’s disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5’ non-coding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with Parkinson’s disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinson’s disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5’ non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.

scholarly journals Common X-chromosome variants are associated with Parkinson’s disease risk

2020 ◽  
Author(s):  
Yann Le Guen ◽  
Valerio Napolioni ◽  
Michael E. Belloy ◽  
Eric Yu ◽  
Lynne Krohn ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
X Chromosome ◽  
Ribosomal Proteins ◽  
Disease Risk ◽  
Meta Analysis ◽  
European Ancestry ◽  
Density Region ◽  
Parental History ◽  
Genome Wide

AbstractObjectiveIdentify genetic variants on the X-chromosome associated with Parkinson’s disease (PD) risk.MethodsWe performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,324 cases, 280,060 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with: (i) PD risk in an independent replication with 1,564 cases and 2,467 controls, and (ii) putamen volume in 33,360 individuals from the UK Biobank.ResultsIn the discovery meta-analysis, we identified: rs7066890 (OR=1.10 [1.06-1.14]; P=2.2×10−9) intron of GPM6B, and rs28602900 (OR=1.10 [1.07-1.14]; P=1.6×10−8) in a high gene density region including RPL10, ATP6A1, FAM50A, PLXNA3. The rs28602900 association with PD was replicated (OR=1.16 [1.03-1.30]; P=0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in GTEx. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.InterpretationWe report the first XWAS of PD and identify two genome-wide significant loci. The rs28602900 association replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10.These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk.

scholarly journals The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1860 ◽  
Author(s):  
Chien Tai Hong ◽  
Lung Chan ◽  
Chyi-Huey Bai
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Meta Analysis ◽  
Motor Fluctuation ◽  
New Drugs ◽  
Caffeine Consumption ◽  
Healthy Cohort ◽  
Adenosine 2A Receptor

Coffee and caffeine are speculated to be associated with the reduced risk of Parkinson’s disease (PD). The present study aimed to investigate the disease-modifying potential of caffeine on PD, either for healthy people or patients, through a meta-analysis. The electronic databases were searched using terms related to PD and coffee and caffeinated food products. Articles were included only upon fulfillment of clear diagnostic criteria for PD and details regarding their caffeine content. Reference lists of relevant articles were reviewed to identify eligible studies not shortlisted using these terms. In total, the present study enrolled 13 studies, nine were categorized into a healthy cohort and the rest into a PD cohort. The individuals in the healthy cohort with regular caffeine consumption had a significantly lower risk of PD during follow-up evaluation (hazard ratio (HR) = 0.797, 95% CI = 0.748–0.849, p < 0.001). The outcomes of disease progression in PD cohorts included dyskinesia, motor fluctuation, symptom onset, and levodopa initiation. Individuals consuming caffeine presented a significantly lower rate of PD progression (HR = 0.834, 95% CI = 0.707–0.984, p = 0.03). In conclusion, caffeine modified disease risk and progression in PD, among both healthy individuals or those with PD. Potential biological benefits, such as those obtained from adenosine 2A receptor antagonism, may require further investigation for designing new drugs.

scholarly journals RIC3 variants are not associated with Parkinson's Disease in large European, Latin American, or East Asian cohorts

2021 ◽  
Author(s):  
Kajsa Brolin ◽  
Sara Bandres Ciga ◽  
Hampton Leonard ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Latin American ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
East Asian ◽  
European Ancestry ◽  
Common Genetic Variants

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD, but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

scholarly journals Establishing the role of rare coding variants in known Parkinson's disease risk loci

2017 ◽  
Vol 59 ◽  
pp. 220.e11-220.e18 ◽  
Author(s):  
Iris E. Jansen ◽  
J. Raphael Gibbs ◽  
Mike A. Nalls ◽  
T. Ryan Price ◽  
Steven Lubbe ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Coding Variants

Glutathione S-transferase T1 and M1 null genotypes and Parkinson’s disease risk: evidence from an updated meta-analysis

2015 ◽  
Vol 36 (9) ◽  
pp. 1559-1565 ◽  
Author(s):  
Hongzhou Liu ◽  
Jie Peng ◽  
Jiajia Gao ◽  
Fang Zheng ◽  
Chaorong Tie
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Meta Analysis ◽  
Glutathione S Transferase

Association between VPS13C rs2414739 polymorphism and Parkinson’s disease risk: A meta-analysis

2021 ◽  
pp. 135879
Author(s):  
Xinling Bai ◽  
Xian Liu ◽  
Xiaoyuan Li ◽  
Wenjian Li ◽  
Anmu Xie
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Meta Analysis

Diet Quality and Risk of Parkinson’s Disease: A Prospective Study and Meta-Analysis

2020 ◽  
pp. 1-11
Author(s):  
Yi-Hsuan Liu ◽  
Gordon L. Jensen ◽  
Muzi Na ◽  
Diane C. Mitchell ◽  
G. Craig Wood ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cohort Study ◽  
Confidence Intervals ◽  
Diet Quality ◽  
Dietary Pattern ◽  
Disease Risk ◽  
Meta Analysis ◽  
Cox Proportional Hazards ◽  
Healthy Dietary Pattern

Background: Several dietary components have been shown to be neuroprotective against risk of neurodegeneration. However, limited observational studies have examined the role of overall diet quality on risk of Parkinson’s disease. Objectives: We examined the associations between diet quality and risk of Parkinson’s disease in a prospective cohort study and meta-analysis. Methods: Included in the cohort study were 3,653 participants (1,519 men and 2,134 women; mean age: 81.5 years) in the Geisinger Rural Aging Study longitudinal cohort in Pennsylvania. Diet quality was assessed using a validated dietary screening tool containing 25 food- and behavior-specific questions in 2009. Potential Parkinson’s cases were identified using electronic health records based on ICD9 (332.*), ICD10 (G20), and Parkinson-related treatments. Hazard ratios (HRs) and 95% confidence intervals (CIs) across diet quality tertiles were calculated using Cox proportional hazards models after adjusting for potential confounders. We further performed a meta-analysis by pooling our study with four published papers on this topic. Random-effects model was utilized to calculate the pooled risk ratios and 95% confidence intervals (CIs). Results: During a mean of 6.94 years of follow-up, 47 incident Parkinson’s cases were documented. Having high diet quality at baseline was associated with lower Parkinson’s disease risk (adjusted HR for the highest vs the lowest diet quality tertile = 0.39; 95% CI: 0.17, 0.89; p-trend = 0.02). The meta-analysis including 140,617 individuals also showed that adherence to high diet quality or a healthy dietary pattern was associated with lower risk of Parkinson’s disease (pooled risk ratio = 0.64; 95% CI: 0.49, 0.83). Conclusion: Having high diet quality or a healthy dietary pattern was associated with lower future risk of Parkinson’s disease.

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