Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson's disease

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's 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's 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 Parkinson's 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. ### Competing Interest Statement The University of Luxembourg has filed the patent No. LU502780 "METHODS FOR STRATIFICATION OF PARKINSON'S DISEASE PATIENTS, SYSTEMS AND USES THEREOF". GA, ZL, RK, PM and AG are listed as inventors. ### Funding Statement Luxembourg National Research Fund (C17/BM/11676395 to RK, AG, PM, EG and GA) Luxembourg National Research Fund (FNR/NCER13/BM/11264123 to RK) Luxembourg National Research Fund (FNR/P13/6682797 to RK) Luxembourg National Research Fund (C21/BM/15850547 to GA) Luxembourg National Research Fund (FNR9631103 to AG) Luxembourg National Research Fund and German Research Council (FNR/DFG 11250962 to PM and AG) Luxembourg National Research Fund and German Research Council (FNR/DFG 11676395 to MS and AAKS) Luxembourg National Research Fund (EU Horizon 2020 programme, grant no. ERAPERMED 2020-314, DIGI-PD to EG). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for this work was given by the National Committee for Ethics in Research in Luxembourg (Comite' National d'Ethique dans la Recherche; CNER #201411/05). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Genetic and clinical data for this manuscript are not publicly available as they are linked to the internal regulations of the Luxembourg Parkinson's Study and COURAGE-PD consortia. Requests for accessing the datasets can be directed to request.ncer-pd@uni.lu and courage@hih-mail.neurologie.uni-tuebingen.de, where dedicated data access committees review the requests and conclude data sharing agreements with prospective users.