Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson's disease
DOI10.5281/zenodo.7973685Zenodo7973685MaRDI QIDQ6691926FDOQ6691926
Dataset published at Zenodo repository.
Giuseppe Arena, Alexandre Baron, Zied Landoulsi, Armelle Vitali, Sylvie Delcambre, Paul Antony, Ashwin Ashok Kumar Sreelatha, Patrick May, Dajana Grossmann, Lukas Pavelka, Anne Grünewald, Dheeraj Reddy Bobbili, Ibrahim Boussaad, Enrico Glaab, Manu Sharma, Rejko Krüger
Publication date: 26 May 2023
Copyright license: Creative Commons Attribution 4.0 International
Background Parkinsons 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 Parkinsons 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 Parkinsons 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 the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinsons Study iPD patients stratified according to the OXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients. Conclusions our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden potentially eligible for future, more tailored mitochondrially targeted treatments.
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