Electronic Resource
Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson\textquoterights disease 2023.05.12.23289877
| العنوان: | Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson\textquoterights disease 2023.05.12.23289877 |
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| المؤلفون: | Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Institute of Health - LIH [research center], Fonds National de la Recherche - FnR [sponsor], German Research Council - DFG [sponsor], Arena, Giuseppe, Landoulsi, Zied, Grossmann, Dajana, Vitali, Armelle, Delcambre, Sylvie, Baron, Alexandre, Antony, Paul, Boussaad, Ibrahim, Bobbili, Dheeraj Reddy, Sreelatha, Ashwin Ashok Kumar, Pavelka, Lukas, Klein, Christine, Seibler, Philip, Glaab, Enrico, Sharma, Manu, Krüger, Rejko, May, Patrick, Grünewald, Anne |
| بيانات النشر: | Cold Spring Harbor Laboratory Press 2023-05-12 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Background Parkinson's disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ~10\% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration.Methods: To capture this mitochondria-related 'missing heritability', we leveraged on existing data from previous genome-wide association studies (GWAS) i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson\textquoterights Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls).Results: Applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk both in the Luxembourg Parkinson\textquoterights Study (odds ratio, OR=1.31[1.14-1.50], p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p=1.5e-29). Functional analyses in primary skin fibroblasts and in |
| مصطلحات الفهرس: | info:eu-repo/semantics/preprint |
| URL: | medRXiv 2023.05.12.23289877 info:eu-repo/grantAgreement/EC/H2020/779282 |
| الاتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | English |
| Other Numbers: | LULUX oai:orbilu.uni.lu:10993/55367 info:doi:10.1101/2023.05.12.23289877 1388546599 |
| المصدر المساهم: | UNIV OF LUXEMBOURG From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1388546599 |
| قاعدة البيانات: | OAIster |
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