scholarly journals Identifying Risk Genes and Interpreting Pathogenesis for Parkinson’s Disease by a Multiomics Analysis

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1100
Author(s):  
Wen-Wen Cheng ◽  
Qiang Zhu ◽  
Hong-Yu Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Regulation ◽  
Regulation Of Transcription ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
Dna Elements

Genome-wide association studies (GWAS) have identified tens of genetic variants associated with Parkinson’s disease (PD). Nevertheless, the genes or DNA elements that affect traits through these genetic variations are usually undiscovered. This study was the first to combine meta-analysis GWAS data and expression data to identify PD risk genes. Four known genes, CRHR1, KANSL1, NSF and LRRC37A, and two new risk genes, STX4 and BST1, were identified. Among them, CRHR1 is a known drug target, indicating that hydrocortisone may become a potential drug for the treatment of PD. Furthermore, the potential pathogenesis of CRHR1 and LRRC37A was explored by applying DNA methylation (DNAm) data, indicating a pathogenesis whereby the effect of a genetic variant on PD is mediated by genetic regulation of transcription through DNAm. Overall, this research identified the risk genes and pathogenesis that affect PD through genetic variants, which has significance for the diagnosis and treatment of PD.

scholarly journals Polymorphisms of ACMSD-TMEM163, MCCC1, and BCKDK-STX1B Are Not Associated with Parkinson’s Disease in Taiwan

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Kuo-Hsuan Chang ◽  
Chiung-Mei Chen ◽  
Yi-Chun Chen ◽  
Hon-Chung Fung ◽  
Yih-Ru Wu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amino Acid ◽  
Genetic Variants ◽  
Transmembrane Protein ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Amino Acid Catabolism ◽  
Genome Wide

Previous genome-wide association studies in Caucasian populations suggest that genetic loci in amino acid catabolism may be associated with Parkinson’s disease (PD). However, these genetic disease associations were limitedly reported in Asian populations. Herein, we investigated the effect of top three PD-associated genetic variants related to amino acid catabolism in Caucasians listed on the top risk loci identified by meta-analysis of genome-wide association studies in PDGene database, including aminocarboxymuconate-semialdehyde decarboxylase- (ACMSD-) transmembrane protein 163 (TMEM163) rs6430538, methylcrotonyl-CoA carboxylase 1 (MCCC1) rs12637471, and branched-chain ketoacid dehydrogenase kinase- (BCKDK-) syntaxin 1B (STX1B) rs14235, by genotyping 599 Taiwanese patients with PD and 598 age-matched control subjects. PD patients demonstrate similar allelic and genotypic frequencies in all tested genetic variants. These ethnic discrepancies of genetic variants suggest a distinct genetic background of amino acid catabolism between Taiwanese and Caucasian PD patients.

scholarly journals Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

2019 ◽  
Vol 18 (12) ◽  
pp. 1091-1102 ◽  
Author(s):  
Mike A Nalls ◽  
Cornelis Blauwendraat ◽  
Costanza L Vallerga ◽  
Karl Heilbron ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Type 2 diabetes as a determinant of Parkinson’s disease risk and progression

2020 ◽  
Author(s):  
Harneek Chohan ◽  
Konstantin Senkevich ◽  
Radhika K Patel ◽  
Jonathan P Bestwick ◽  
Benjamin M Jacobs ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Observational Studies ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Summary Data

ABSTRACTObjectiveTo investigate type 2 diabetes mellitus (T2DM) as a determinant of Parkinson’s disease (PD) through a meta-analysis of observational and genetic summary data.MethodsA systematic review and meta-analysis of observational studies was undertaken by searching six databases. We selected the highest quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate causal effects of genetic liability towards T2DM on PD risk and progression, using summary data derived from genome-wide association studies.ResultsIn the observational part of the study, nine studies were included in the risk meta-analysis and four studies were included in the progression meta-analysis. Pooled effect estimates revealed that T2DM was associated with an increased risk of PD (OR 1.21, 95% CI 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (SMD 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD −0.92, 95% CI −1.50 – −0.34). Using MR we found supportive evidence for a causal effect of diabetes on PD risk (IVW OR 1.08, 95% CI 1.02-1.14; p=0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; p=0.032), but not for cognitive progression.ConclusionUsing meta-analysis of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk, and new evidence to support a role in PD progression. Treatment of diabetes may be an effective strategy to prevent or slow progression of PD.

scholarly journals ERASE: Extended Randomization for assessment of annotation enrichment in ASE datasets

2019 ◽  
Author(s):  
Karishma D’Sa ◽  
Regina H. Reynolds ◽  
Sebastian Guelfi ◽  
David Zhang ◽  
Sonia Garcia Ruiz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Gwas Data ◽  
Genome Wide Association Studies ◽  
Specific Expression ◽  
Individual Snps

AbstractGenome-wide association studies (GWAS) have identified thousands of genetic variants associated with various human phenotypes and many of these loci are thought to act at a molecular level by regulating gene expression. Detection of allele specific expression (ASE), namely preferential usage of an allele at a transcribed locus, is an increasingly important means of studying the genetic regulation of gene expression. However, there are currently a paucity of tools available to link ASE sites with GWAS risk loci. Existing integration methods first use ASE sites to infer cis-acting expression quantitative trait loci (eQTL) and then apply eQTL-based approaches. ERASE is a method that assesses the enrichment of risk loci amongst ASE sites directly. Furthermore, ERASE enables additional biological insights to be made through the addition of other SNP level annotations. ERASE is based on a randomization approach and controls for read depth, a significant confounder in ASE analyses. In this paper, we demonstrate that ERASE can efficiently detect the enrichment of eQTLs and risk loci within ASE data and that it remains sensitive even when used with underpowered GWAS datasets. Finally, using ERASE in combination with GWAS data for Parkinson’s disease and data on the splicing potential of individual SNPs, we provide evidence to suggest that risk loci for Parkinson’s disease are enriched amongst ASEs likely to affect splicing. Thus, we show that ERASE is an important new tool for the integration of ASE and GWAS data, capable of providing novel insights into the pathophysiology of complex diseases.

scholarly journals Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

2020 ◽  
Author(s):  
Marc P.M. Soutar ◽  
Daniela Melandri ◽  
Emily Annuario ◽  
Amy E. Monaghan ◽  
Natalie J. Welsh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Functional Significance ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Lysine Acetylation ◽  
Screening Assay ◽  
Risk Genes ◽  
Genome Wide

ABSTRACTParkinson’s disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings establish PINK1-mitophagy as a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. Our data provide evidence that this assignment is likely to be incorrect and that variability at KANSL1 underpins this association. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

scholarly journals Association of GAK rs1564282 With Susceptibility to Parkinson’s Disease in Chinese Populations

2021 ◽  
Vol 12 ◽  
Author(s):  
He Li ◽  
Chen Zhang ◽  
Yong Ji
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Odds Ratio ◽  
Association Studies ◽  
Meta Analysis ◽  
Significant Heterogeneity ◽  
Genome Wide Association Studies ◽  
Chinese Populations ◽  
Genome Wide ◽  
Significant Publication Bias

The susceptibility of the GAK rs1564282 variant in Parkinson’s disease (PD) in Europeans was identified using a series of published genome-wide association studies. Recently, some studies focused on the association between rs1564282 and PD risk in Chinese populations but with inconsistent results. Thus, we conducted an updated meta-analysis with a total of 7,881 samples (4,055 PD cases and 3,826 controls) from eligible studies. After excluding significant heterogeneity, we showed that the rs1564282 variant was significantly associated with PD in Chinese populations (p = 1.00E-04, odds ratio = 1.28 and 95% confidence interval = 1.16–1.42). The sensitivity analysis showed that the association between rs1564282 and PD was not greatly influenced, and there was no significant publication bias among the included studies. Consequently, this meta-analysis indicates that the GAK rs1564282 variant is significantly associated with susceptibility to PD in Chinese populations.

scholarly journals A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

2017 ◽  
Vol 49 (10) ◽  
pp. 1511-1516 ◽  
Author(s):  
Diana Chang ◽  
◽  
Mike A Nalls ◽  
Ingileif B Hallgrímsdóttir ◽  
Julie Hunkapiller ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide
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