Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease

Giuseppe Arena*, Zied Landoulsi, Dajana Grossmann, Thomas Payne, Armelle Vitali, Sylvie Delcambre, Alexandre Baron, Paul Antony, Ibrahim Boussaad, Dheeraj Reddy Bobbili, Ashwin Ashok Kumar Sreelatha, Lukas Pavelka, Nico J Diederich, Christine Klein, Philip Seibler, Enrico Glaab, Thomas Foltynie, Oliver Bandmann, Manu Sharma, Rejko Krüger*Patrick May, Anne Grünewald

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective: The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. Methods: We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case–control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. Results: Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14–1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18–1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. Interpretation: OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024.

Original languageEnglish
Pages (from-to)133-149
JournalAnnals of Neurology
Volume96
Issue number1
Early online date20 May 2024
DOIs
Publication statusPublished - Jul 2024

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