Common genetic variants associated with Parkinson’s disease display widespread signature of epigenetic plasticity

Sharma, Amit; Osato, Naoki; Liu, Hongde; Asthana, Shailendra; Dakal, Tikam Chand; Ambrosini, Giovanna; Bücher, Philipp; Schmitt, Imke; Wüllner, Ullrich

doi:10.1038/s41598-019-54865-w

Cited by 20 publications

(11 citation statements)

References 48 publications

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“…Similar observations have been reported previously 14,25,29 . However, the mechanism underlying this differential regulation remains unclear and is likely associated with the existence of 2 adjacent DNA methyltransferase 1 docking sites 30 …”

Section: Discussionsupporting

confidence: 85%

“…14,25,29 However, the mechanism underlying this differential regulation remains unclear and is likely associated with the existence of 2 adjacent DNA methyltransferase 1 docking sites. 30 One concern is whether the status of DNA methylation in peripheral blood cells can serve as a biomarker for iRBD, in which cell damage primarily occurs in the brain. A few studies have already illustrated an association between peripheral DNA methylation and changes in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

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Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion

Hao

Zhang

et al. 2020

Movement Disorders

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Background Hypomethylation of intron 1 of the α‐synuclein (SNCA) gene has been extensively reported in the blood of patients with α‐synucleinopathies. Idiopathic rapid eye movement sleep behavior disorder represents a prodromal stage of α‐synucleinopathies. Methylation of α‐synuclein intron 1 in idiopathic rapid eye movement sleep behavior disorder patients is largely unexplored. The objective of the current study was to assess blood α‐synuclein intron 1 methylation in patients and to explore it as a potential biomarker to predict phenoconversion and monitor disease progression. Methods Seventy‐eight polysomnography‐confirmed patients and 74 healthy controls were enrolled. After an average of 3.75 years of follow up, 16 patients converted to neurodegenerative diseases (converters), whereas 59 did not (nonconverters). Blood DNA was obtained at baseline from all participants, as well as at the follow‐up visit for 27 patients. DNA methylation levels were determined using bisulfite pyrosequencing methods and were compared between patients and healthy controls, converters and nonconverters, and baseline and follow‐up visits. Results Hypomethylation at cytosine‐phosphate‐guanine 10, 11, 12, 13, and 17 was found in patients compared with healthy controls. Hypomethylation at cytosine‐phosphate‐guanine 17 was associated with an increased risk of clinical phenoconversion, which was further enhanced with the presence of subtle motor abnormalities. In addition, it appeared that later reduction in methylation levels at cytosine‐phosphate‐guanine 14, 15, and 16 was associated with disease progression. Conclusions Peripheral blood α‐synuclein intron 1 was hypomethylated in idiopathic rapid eye movement sleep behavior disorder patients. α‐Synuclein methylation levels may be useful biomarkers to screen patients, predict phenoconversion, and monitor disease progression. © 2020 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion

Hao

Zhang

et al. 2020

Movement Disorders

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“…Disruptive variants at these loci could be contributing to diseaseassociated changes in the deposition of these marks and, in extension, contribute to an intermediate disease phenotype. Such interplay was recently also shown at the SNCA locus, where a differentially methylated region in PD patients (Jowaed et al 2010) was also found to contain PD-associated variants and that this site is a target for DNA demethylases (Sharma et al 2019). These findings highlight the complex interconnection of regulatory marks and genetics and the inherent difficulty to dissociate environment-or diseaseassociated contributions from genetic effects on DNA and histone modifications.…”

Section: Epigenetic Changes In Neurodegenerative Diseasesmentioning

confidence: 64%

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

2020

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Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease-and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

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“…Despite a large number of studies that have addressed the local/global DNA methylation changes in multiple human cancers and other diseases [11,15,16], the key link showing the switch towards the dynamics of DNA hypo-/hypermethylation is still missing. Perhaps, defining the distinct roles of hypo-and hypermethylation within the same individual might help to undermine their potential consequences.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation and Bladder Cancer: Where Genotype does not Predict Phenotype

Sharma

Reutter

Ellinger

2020

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Nearly three decades ago, the association between Bladder cancer (BC) and DNA methylation has initially been reported. Indeed, in the recent years, the mechanism connecting these two has gained deeper insights. Still, the mediocre performance of DNA methylation markers in the clinics raises the major concern. Strikingly, whether it is the inter-individual methylation variations or the paucity of knowledge about methylation fingerprints lying within histologically distinct subtypes of BC requires critical discussion. In the future, besides identifying the initial causative factors, it will be important to illustrate the cascade of events that determines the fraction of the genome to convey altered methylation patterns specific towards each cancer type.

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Common genetic variants associated with Parkinson’s disease display widespread signature of epigenetic plasticity

Cited by 20 publications

References 48 publications

Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion

Hypomethylation of SNCA in Idiopathic REM Sleep Behavior Disorder Associated With Phenoconversion

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

DNA Methylation and Bladder Cancer: Where Genotype does not Predict Phenotype

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