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

Abstract

AbstractBackgroundParkinson’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.Methodsto 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).Resultsapplying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulatingOxidative 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 theOXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p< 0.05). Finally, we also demonstrated that iPD patients with highOXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients.Conclusionsour 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.