TY - JOUR
T1 - Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease
AU - Arena, Giuseppe
AU - Landoulsi, Zied
AU - Grossmann, Dajana
AU - Payne, Thomas
AU - Vitali, Armelle
AU - Delcambre, Sylvie
AU - Baron, Alexandre
AU - Antony, Paul
AU - Boussaad, Ibrahim
AU - Bobbili, Dheeraj Reddy
AU - Sreelatha, Ashwin Ashok Kumar
AU - Pavelka, Lukas
AU - J Diederich, Nico
AU - Klein, Christine
AU - Seibler, Philip
AU - Glaab, Enrico
AU - Foltynie, Thomas
AU - Bandmann, Oliver
AU - Sharma, Manu
AU - Krüger, Rejko
AU - May, Patrick
AU - Grünewald, Anne
N1 - Acknowledgements
This study was funded by the Luxembourg National Research Fund (C17/BM/11676395 to RK, PM and AG; C21/BM/15850547 to GA; ERAPERMED 2020-314 to EG; FNR/NCER13/BM/11264123 and FNR/P13/6682797 to RK; INTER/DFG/19/14429377 to PM and AG; FNR9631103 to AG) and the German Research Council (FNR/DFG 11676395 to MS and AAKS). Research was also supported and co-funded by the National Institute for Health and Care Research (NIHR), and the Sheffield Biomedical Research Centre (BRC)/NIHR Sheffield Clinical Research Facility (CRF). It was also supported by the NIHR UCLH Biomedical Research Centre, and the NIHR UCLH Clinical Research Facility–Leonard Wolfson Experimental Neurology Centre. TP and OB are supported by the JP Moulton Chari- table Foundation and The Cure Parkinson’s Trust. The work was also supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, part of the U.S. National Institutes of Health (program number 1ZIANS003154).
We thank all participants of the Luxembourg Parkinson’s Study for their essential support of our research. Furthermore, we acknowledge the joint effort of the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) Consortium members from the partner institutions Luxembourg Centre for Systems Biomedicine, Luxembourg Institute of Health, Centre Hospitalier de Luxembourg and Laboratoire National de Santé generally contributing to the Luxembourg Parkinson’s Study, as well as all members of the international COURAGE-PD consortium (Table S5).
Publisher Copyright:
© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/7
Y1 - 2024/7
N2 - 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;96:133–149.
AB - 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;96:133–149.
UR - https://www.scopus.com/pages/publications/85193590552
UR - https://pubmed.ncbi.nlm.nih.gov/38767023
U2 - 10.1002/ana.26949
DO - 10.1002/ana.26949
M3 - Article
C2 - 38767023
AN - SCOPUS:85193590552
SN - 0364-5134
VL - 96
SP - 133
EP - 149
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -