Reference : Missing heritability in Parkinson’s disease: the emerging role of non‑coding genetic ...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Systems Biomedicine
http://hdl.handle.net/10993/43016
Missing heritability in Parkinson’s disease: the emerging role of non‑coding genetic variation
English
Ohnmacht, Jochen mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Sinkkonen, Lasse mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Krüger, Rejko mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
4-Apr-2020
Journal of Neural Transmission
Springer
Yes (verified by ORBilu)
International
0300-9564
1435-1463
Vienna
Germany
[en] Gene regulation ; Genetic modifier ; Genetic susceptibility ; Genome-wide association studies ; Non-coding variation ; Parkinson’s disease ; Polygenic risk scores
[en] 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.
Luxembourg Centre for Systems Biomedicine (LCSB) ; Department of Life Sciences and Medicine (DLSM)
Luxembourg National Research Fund ; Fondation du Pélican de Mie et Pierre Hippert-Faber
Researchers ; Professionals ; Students
http://hdl.handle.net/10993/43016
10.1007/s00702-020-02184-0
https://link.springer.com/article/10.1007/s00702-020-02184-0
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H2020 ; 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease

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