[en] [en] 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.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) Luxembourg Centre for Systems Biomedicine (LCSB): Molecular & Functional Neurobiology (Grünewald Group)
Disciplines :
Genetics & genetic processes Biochemistry, biophysics & molecular biology Neurology Human health sciences: Multidisciplinary, general & others
LANDOULSI, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
GROSSMANN, Dajana ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience ; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
Payne, Thomas; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
VITALI, Armelle ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
DELCAMBRE, Sylvie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Molecular and Functional Neurobiology > Team Anne GRÜNEWALD
BARON, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
BOUSSAAD, Ibrahim ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Sreelatha, Ashwin Ashok Kumar; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
PAVELKA, Lukas ; University of Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg ; Parkinson Research Clinic, Centre Hospitalier du Luxembourg, Luxembourg, Luxembourg
J Diederich, Nico; Department of Neurosciences, Centre Hospitalier de Luxembourg, Strassen, Luxembourg
Klein, Christine ; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Seibler, Philip; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Foltynie, Thomas; Department of Clinical and Movement Neurosciences, Institute of Neurology, University College London, London, UK
Bandmann, Oliver ; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
Sharma, Manu ; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Luxembourg Institute of Health (LIH) > Transversal Translational Medicine ; Centre Hospitalier de Luxembourg > Parkinson Research Clinic
FNR11264123 - Ncer-pd, 2015 (01/01/2015-30/11/2020) - Rejko Krüger FNR11676395 - Mitochondrial Risk Factors In Parkinson's Disease, 2017 (01/03/2018-31/08/2021) - Rejko Krüger FNR14429377 - Reduced Penetrance In Hereditary Movement Disorders: Elucidating Mechanisms Of Endogenous Disease Protection, 2020 (01/07/2020-30/06/2023) - Anne Grünewald FNR15850547 - Pink1-related Molecular Mechanisms To Dissect The Connection Between Type 2 Diabetes And Insulin Resistance In Parkinson’S Disease, 2021 (01/01/2022-31/08/2024) - Giuseppe Arena FNR11676395 - Mitochondrial Risk Factors In Parkinson's Disease, 2017 (01/03/2018-31/08/2021) - Rejko Krüger FNR6682797 - Comprehensive Assessment Of Endophenotypes In Neurodegenerative Diseases - Translating Impaired Molecular Signalling Pathways Into Novel Therapeutic Strategies For Parkinson’S Disease, 2013 (01/06/2014-31/05/2019) - Rejko Krüger FNR14599012 - Validating Digital Biomarkers For Better Personalized Treatment Of Parkinson’S Disease, 2020 (01/05/2021-30/04/2024) - Enrico Glaab
Name of the research project :
Mito-Risk NCER-PD Courage-PD
Funders :
National Institute for Health and Care Research (NIHR) Sheffield Biomedical Research Centre (BRC)/NIHR Sheffield Clinical Research Facility (CRF) JP Moulton Charitable Foundation The Cure Parkinson's Trust National Institute of Neurological Disorders and Stroke Union Européenne
Funding text :
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 Charitable 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).
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