[en] We investigated the role of copy number variations (CNVs) in Parkinson's disease (PD) using genotyping data from 10,815 patients (2731 early-onset PD, EOPD) and 8901 controls from the COURAGE-PD consortium. CNVs were analyzed using a sliding window genome-wide association and burden approach. No genome-wide significant CNVs were detected in the overall cohort, but a robust deletion spanning exons 2-6 of PRKN was identified in EOPD cases, validated by MLPA, and replicated in the GP2 dataset (23,089 cases, 18,824 controls). CNV burden was significantly enriched in PD-related genes, primarily driven by PRKN, with the strongest effect observed in EOPD. PRKN CNV carriers showed earlier age at onset, confirmed by survival analysis. No association was observed for genome-wide or large CNV burden. Our findings reinforce the pivotal role of PRKN deletions in early-onset PD and highlight the need for high-resolution CNV analysis in large cohorts to uncover additional rare contributors to PD risk.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes Neurology
Author, co-author :
LANDOULSI, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Bioinformatics Core > Research BioCore ; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg. zied.landoulsi@lih.lu
Sreelatha, Ashwin Ashok Kumar; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany
Kuznetsov, Nicole; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging, National Institutes of Health, Bethesda, USA ; DataTecnica LLC, Washington, DC, 20037, USA
Schulte, Claudia; Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Montanucci, Ludovica; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Leu, Costin; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK ; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Niestroj, Lisa-Marie; Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, Cologne, Germany
HASSANIN, Emadeldin ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Radivojkov-Blagojevic, Milena; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Lichtner, Peter; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Portugal, Berta; Department of Precision Health, Luxembourg Institute of Health, Strassen, Luxembourg
Edsall, Connor; Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, 20892, USA
Krüger, Jens; Group of Applied Bioinformatics, University of Tübingen, Tübingen, Germany
Hernandez, Dena G; Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, 20892, USA
Blauwendraat, Cornelis; Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, 20892, USA
Mellick, George D; Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland, Australia
Zimprich, Alexander; Department of Neurology, Medical University of Vienna, Vienna, Austria
Pirker, Walter; Department of Neurology, Klinik Ottakring, Vienna, Austria
Tan, Manuela; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
Rogaeva, Ekaterina; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
Lang, Anthony; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada ; Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada ; Division of Neurology, University of Toronto, Toronto, Ontario, Canada ; Krembil Brain Institute, Toronto, Ontario, Canada
Koks, Sulev; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Australia ; Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia
Taba, Pille; Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia ; Neurology Clinic, Tartu University Hospital, Tartu, Estonia
Lesage, Suzanne; Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France
Brice, Alexis; Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France
Corvol, Jean-Christophe; Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France ; Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France
Chartier-Harlin, Marie-Christine; Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Lille Neurosciences & Cognition, F-59000, Lille, France
Mutez, Eugenie; Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Lille Neurosciences & Cognition, F-59000, Lille, France
Brockmann, Kathrin; Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Deutschländer, Angela B; Department of Neurology, Ludwig Maximilians University of Munich, Munich, Germany ; Department of Neurology, Max Planck Institute of Psychiatry, Munich, Germany ; Department of Neurology and Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL, USA
Hadjigeorgiou, Georges M; Department of Neurology, Medical School, University of Cyprus, Nicosia, Cyprus ; Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
Dardiotis, Efthimos; Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
Stefanis, Leonidas; Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece ; st1 Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Simitsi, Athina Maria; st1 Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Valente, Enza Maria; Department of Molecular Medicine, University of Pavia, Pavia, Italy ; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Mondino Foundation, Pavia, Italy
Petrucci, Simona; UOC Medical Genetics and Advanced Cell Diagnostics, S. Andrea University Hospital, Rome, Italy ; Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
Straniero, Letizia; Department of Biomedical Sciences - Humanitas University, Milan, Italy
Zecchinelli, Anna; Parkinson Institute, Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano, Italia
Pezzoli, Gianni; Parkinson Institute, Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano, Italia ; Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy
Brighina, Laura; Department of Neurology, San Gerardo Hospital, Milan, Italy ; Center for Neuroscience, University of Milano Bicocca, Monza, Italy
Ferrarese, Carlo; Department of Neurology, San Gerardo Hospital, Milan, Italy ; Center for Neuroscience, University of Milano Bicocca, Monza, Italy
Annesi, Grazia; Institute for Biomedical Research and Innovation, National Research Council, Cosenza, Italy
Quattrone, Andrea; Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
Gagliardi, Monica; Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Graecia University, Catanzaro, Italy
Burbulla, Lena F; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA ; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Matsuo, Hirotaka; Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, 359-8513, Japan
Nakayama, Akiyoshi; Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, 359-8513, Japan
Hattori, Nobutaka; Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
Nishioka, Kenya; Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
Chung, Sun Ju; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Kim, Yun Joong; Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
Pavelka, Lukas; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg
Kolber, Pierre; Centre Hospitalier du Luxembourg, Parkinson Research Clinic, Luxembourg, Luxembourg
van de Warrenburg, Bart Pc; Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands
Bloem, Bastiaan R; Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Nijmegen, The Netherlands
Singleton, Andrew B; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging, National Institutes of Health, Bethesda, USA ; Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, 20892, USA
Vitale, Dan; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging, National Institutes of Health, Bethesda, USA ; DataTecnica LLC, Washington, DC, 20037, USA
Toft, Mathias; Department of Neurology, Oslo University Hospital, Oslo, Norway
Pihlstrom, Lasse; Department of Neurology, Oslo University Hospital, Oslo, Norway
Guedes, Leonor Correia; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal ; Department of Neurosciences and Mental Health, Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN), Lisbon, Portugal
Ferreira, Joaquim J; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal ; Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Bardien, Soraya; Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa ; South African Medical Research Council / Stellenbosch University Genomics of Brain Disorders Research Unit, Stellenbosch University, Cape Town, South Africa
Carr, Jonathan; Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
Tolosa, Eduardo; Parkinson's disease &Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII), Barcelona, Spain
Ezquerra, Mario; Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona, ES-08036, Barcelona, Catalonia, Spain
Pastor, Pau; Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain ; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain
Wirdefeldt, Karin; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Pedersen, Nancy L; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Ran, Caroline; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Belin, Andrea C; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Puschmann, Andreas; Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Getingevägen 4, 221 85, Lund, Sweden
Clarke, Carl E; University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom
Morrison, Karen E; Faculty of Medicine, Health and Life Sciences, Queens University, Belfast, United Kingdom
Krainc, Dimitri; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA
Farrer, Matt J; Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
Lal, Dennis; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA ; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA ; Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Gasser, Thomas; Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg ; Centre Hospitalier du Luxembourg, Parkinson Research Clinic, Luxembourg, Luxembourg
Sharma, Manu; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany. manu.sharma@uni-tuebingen.de
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease (COURAGE-PD) consortium
FNR11264123 - NCER-PD - Ncer-pd, 2015 (01/06/2015-31/05/2023) - Rejko Krüger FNR14429377 - ProtectMove II - Reduced Penetrance In Hereditary Movement Disorders: Elucidating Mechanisms Of Endogenous Disease Protection, 2020 (01/07/2020-30/06/2023) - Anne Grünewald FNR16394868 - MechEpi-2 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/01/2022-31/12/2024) - Alexander Skupin
Funders :
FNR - Fonds National de la Recherche Luxembourg MJFF - Michael J. Fox Foundation for Parkinson's Research DFG - German Research Foundation
Funding text :
This study used data from the Courage-PD consortium, conducted under a partnership agreement among 35 studies. The Courage-PD consortium is supported by the EU Joint Program for Neurodegenerative Disease research (JPND https://neurodegenerationresearch.eu). This project was supported by the Global Parkinson’s Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research (MJFF). P.M. was funded by the Fonds National de Recherche (FNR), Luxembourg, as part of the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD, FNR11264123). Z.L. and P.M. were supported by the DFG Research Unit FOR2715 (INTER/DFG/17/11583046), FOR2488 (INTER/DFG/19/14429377) and the National Centre for Excellence in Research on Parkinson’s disease (NCER-PD). A.B.S., D.G.H., and C.E. are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949. E.R. is funded by the Canadian Consortium on Neurodegeneration in Aging. S.K. is funded by MSWA. P.T. is the recipient of an Estonian Research Council Grant PRG957. E.M.V. is funded by the Italian Ministry of Health (Ricerca Corrente 2021). S.B. and J.C. are supported by grants from the National Research Foundation of South Africa (grant number: 106052); the South African Medical Research Council (Self-Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF-DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; and Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town. P. Pastor have received funding from the Spanish Ministry of Science and Innovation (SAF2013-47939-R). K.W. and N.L.P. are funded by the Swedish Research Council, grant numbers K2002-27X-14056-02B, 521-2010-2479, 521-2013-2488, and 2017-02175. N.L.P. is funded by the National Institutes of Health, grant numbers ES10758 and AG 08724. C.R. is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, and Karolinska Institutet Research Fund. A.C.B. is funded by the Swedish Brain Foundation, Swedish Research Council, and Karolinska Institutet Research Funds. M.T. is funded by the Parkinson's UK. M.S. was supported by grants from the German Research Council (DFG/SH 599/6-1), MSA Coalition, and The Michael J. Fox Foundation (USA Genetic Diversity in PD Program: GAP-India Grant ID: 17473). A.E. reports grants from Agence nationale de recherche (ANR), The Michael J. Fox Foundation, Plan Ecophyto (French Ministry of Agriculture), and France Parkinson outside the submitted work. PG GEN sample collection was funded by the MRC and UK Medical Research Council (C.E.C. and K.E.M.). The sponsors had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the paper for publication.
