scholarly journals Prioritizing Parkinson’s Disease genes using population-scale transcriptomic data

2017 ◽  
Author(s):  
Yang I Li ◽  
Garrett Wong ◽  
Jack Humphrey ◽  
Towfique Raj
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Late Onset ◽  
Association Studies ◽  
Disease Genes ◽  
Genome Wide Association Studies ◽  
Gene Associations ◽  
Causal Genes ◽  
Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have identified over 41 susceptibility loci associated with late-onset Parkinson’s Disease (PD) but identifying putative causal genes and the underlying mechanisms remains challenging. To address this, we leveraged large-scale transcriptomic datasets to prioritize genes that are likely to affect PD. We found 29 gene associations in peripheral monocytes, and 44 gene associations whose expression or differential splicing in prefrontal cortex is associated with PD. This includes many novel genes but also known associations such as MAPT, for which we found that variation in exon 3 splicing explains the common genetic association. Genes identified in our analyses are more likely to interact physically with known PD genes and belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.

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 > 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.

What Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease

2011 ◽  
Vol 91 (4) ◽  
pp. 1161-1218 ◽  
Author(s):  
Olga Corti ◽  
Suzanne Lesage ◽  
Alexis Brice
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Association Studies ◽  
Lewy Bodies ◽  
Mendelian Inheritance ◽  
Model Systems ◽  
Motor Disorder ◽  
Genome Wide Association Studies ◽  
New Genes

Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.

scholarly journals Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

2020 ◽  
Author(s):  
Brian M. Schilder ◽  
Towfique Raj
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Fine Mapping ◽  
Disease Susceptibility ◽  
Disease Risk ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Causal Variants ◽  
Underlying Mechanisms

AbstractRecent genome-wide association studies have identified 78 loci associated with Parkinson’s Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson’s-associated loci using four different statistical and functional fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disrupt LRRK2 and FCGR2A regulatory elements in microglia, MBNL2 enhancers in oligodendrocytes, and DYRK1A enhancers in neurons. Finally, we confirmed the functional relevance of fine-mapped SNPs using a suite of in silico validation approaches. Together, these results provide a robust list of likely causal variants underlying Parkinson’s Disease risk for further mechanistic studies.

scholarly journals Modeling Parkinson’s Disease: Not Only Rodents?

2021 ◽  
Vol 13 ◽  
Author(s):  
Maria Shadrina ◽  
Petr Slominsky
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Biological Fluids ◽  
Association Studies ◽  
Mammalian Species ◽  
Pathological Process ◽  
Disease Genes ◽  
Genome Wide Association Studies ◽  
Biological Studies

Parkinson’s disease (PD) is a common chronic progressive multifactorial neurodegenerative disease. In most cases, PD develops as a sporadic idiopathic disease. However, in 10%–15% of all patients, Mendelian inheritance of the disease is observed in an autosomal dominant or autosomal recessive manner. To date, mutations in seven genes have been convincingly confirmed as causative in typical familial forms of PD, i.e., SNCA, LRRK2, VPS35, PRKN, PINK1, GBA, and DJ-1. Family and genome-wide association studies have also identified a number of candidate disease genes and a common genetic variability at 90 loci has been linked to risk for PD. The analysis of the biological function of both proven and candidate genes made it possible to conclude that mitochondrial dysfunction, lysosomal dysfunction, impaired exosomal transport, and immunological processes can play important roles in the development of the pathological process of PD. The mechanisms of initiation of the pathological process and its earliest stages remain unclear. The study of the early stages of the disease (before the first motor symptoms appear) is extremely complicated by the long preclinical period. In addition, at present, the possibility of performing complex biochemical and molecular biological studies familial forms of PD is limited. However, in this case, the analysis of the state of the central nervous system can only be assessed by indirect signs, such as the level of metabolites in the cerebrospinal fluid, peripheral blood, and other biological fluids. One of the potential solutions to this problem is the analysis of disease models, in which it is possible to conduct a detailed in-depth study of all aspects of the pathological process, starting from its earliest stages. Many modeling options are available currently. An analysis of studies published in the 2000s suggests that toxic models in rodents are used in the vast majority of cases. However, interesting and important data for understanding the pathogenesis of PD can be obtained from other in vivo models. Within the framework of this review, we will consider various models of PD that were created using various living organisms, from unicellular yeast (Saccharomyces cerevisiae) and invertebrate (Nematode and Drosophila) forms to various mammalian species.

scholarly journals Association between NMD3 and symptoms of Parkinson's disease in Chinese

2019 ◽  
Author(s):  
Hui Wu ◽  
Hui Li ◽  
Zhiqiang Shi ◽  
Jiajia Tang ◽  
Shuya Mei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Rating Scale ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Southern Chinese ◽  
Genome Wide ◽  
Hamilton Anxiety Rating Scale ◽  
Meta Analyses

Abstract Bcakground: Parkinson's disease (PD) is a progresasive neurodegenerative movement disorder which is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Large-scale meta-analyses of genome-wide association studies (GWAS) have identified few susceptibility loci in sporadic PD. The aim of this study was to investigate the association between NMD3 single nucleotide polymorphism (SNP) and symptoms of PD patients in southern Chinese. Methods: A total of 217 PD patients were recruited in this study and were genotyped by using SNaPshot technique and the polymer chain reaction. All subjects were evaluated by Mini-Mental State Examination (MMSE), Beijing version Montreal Cognitive Assessment (MoCA), Sniffin’ Sticks 16 (SS-16), Hamilton anxiety rating scale, Hamilton depression rating scale, 39-item Parkinson's disease Questionnaire (PDQ-39) and MDS Unified PD Rating Scale (MDS-UPDRS). Results: NMD3 rs34016896 (T) carriers have worse cognitive function (MMSE: p 0.042, NMD3wildtype: 27.44 ± 2.89, NMD3 carriers: 26.31 ± 3.79; MoCA: p 0.005, NMD3 wildtype: 23.15 ±4.20, NMD3 carriers: 20.75 ± 6.68). Conclusions: The recessive and overdominant model of NMD3 rs34016896 was associated with cognitive impairment in PD patients.

scholarly journals Gene4PD: a comprehensive genetic database of Parkinson's disease

2020 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Permutation Test ◽  
Association Studies ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Abstract BackgroundParkinson'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).MethodsBy 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, differential expression genes, and differential DNA methylation genes) and clinical data in PD. A weighted scoring system was employed to prioritize PAGs. Permutation test and protein-protein interaction network was used to evaluate the interconnectivity and functional correlation among the PAGs. The relationship between AAO and PAGs was further analyzed. A PHP-based web framework was used to construct a database. ResultWe integrated five layers of genetic data 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, which also highlighting the reliability of these genetic data for 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 (GCH1, PINK1, PRKN, FBXO7, ATP13A2) 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.ConclusionGene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.Availability and Implementation: Gene4PD can be freely accessed at http://genemed.tech/gene4pd.

scholarly journals The Parkinson’s Disease GWAS Locus Browser

2020 ◽  
Author(s):  
Francis P. Grenn ◽  
Jonggeol J. Kim ◽  
Mary B. Makarious ◽  
Hirotaka Iwaki ◽  
Anastasia Illarionova ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Association Studies ◽  
Age At Onset ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Risk Variants ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a neurodegenerative disease with an often complex genetic component identifiable by genome-wide association studies (GWAS). The most recent large scale PD GWASes have identified more than 90 independent risk variants for PD risk and progression across 80 loci. One major challenge in current genomics is identifying the causal gene(s) and variant(s) from each GWAS locus. Here we present a GWAS locus browser application that combines data from multiple databases to aid in the prioritization of genes associated with PD GWAS loci. We included 92 independent genome-wide significant signals from multiple recent PD GWAS studies including the PD risk GWAS, age-at-onset GWAS and progression GWAS. We gathered data for all 2336 genes within 1Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Our aim is that the information contained in this browser (https://pdgenetics.shinyapps.io/GWASBrowser/) will assist the PD research community with the prioritization of genes for follow-up functional studies and as potential therapeutic targets.

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.

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