[en] BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.
OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID.
METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID.
RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147).
CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care.
Centre de recherche :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) LIH - Luxembourg Institute of Health
Disciplines :
Neurologie Génétique & processus génétiques
Auteur, co-auteur :
Sosero, Yuri L; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada
Bandres-Ciga, Sara ; Department of Health and Human Services, Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes on Health, Bethesda, Maryland, USA
Ferwerda, Bart; Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Tocino, Maria T P; Servicio de Neurología y Neurofisiología Clínica, Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Department of Neurobiology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Belloso, Dìaz R; Servicio de Neurología y Neurofisiología Clínica, Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Department of Neurobiology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Gómez-Garre, Pilar ; Servicio de Neurología y Neurofisiología Clínica, Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Department of Neurobiology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Faouzi, Johann; Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France ; Department of Economics and Statistics, CREST, ENSAI, Campus de Ker-Lann, Bruz Cedex, France
Taba, Pille; Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
PAVELKA, Lukas ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Strassen, Luxembourg
Marques, Tainà M; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
GOMES, Clarissa ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
KOLODKIN, Alexey ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Bioinformatics Core > R3 and IT infrastructure ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
MAY, Patrick ; University of Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg ; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Strassen, Luxembourg
Milanowski, Lukasz M; Department of Neurology Faculty of Health Science, Medical University of Warsaw, Warsaw, Poland ; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
Wszolek, Zbigniew K ; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
Uitti, Ryan J; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
Heutink, Peter; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
van Hilten, Jacobus J; Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
Simon, David K ; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
Eberly, Shirley; Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Alvarez, Ignacio; Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain
Krohn, Lynne; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada
Yu, Eric; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada
Freeman, Kathryn; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada
Rudakou, Uladzislau; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada
Ruskey, Jennifer A; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
Asayesh, Farnaz; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
Menéndez-Gonzàlez, Manuel; Facultad de Medicina y Ciencias de la Salud, Universidad de Oviedo, Oviedo, Spain ; Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain ; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
Pastor, Pau; Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain ; Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
Ross, Owen A ; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Centre Hospitalier de Luxembourg (CHL) > Parkinson Research Clinic ; Luxembourg Institute of Health (LIH), > Transversal Translational Medicine
NCER‐PD Consortium
Corvol, Jean-Christophe ; Department of Economics and Statistics, CREST, ENSAI, Campus de Ker-Lann, Bruz Cedex, France
Koks, Sulev ; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Australia ; Neurological and Translational Science, Perron Institute, Nedlands, Australia
Mir, Pablo ; Servicio de Neurología y Neurofisiología Clínica, Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Department of Neurobiology, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain ; Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
De Bie, Rob M A ; Department of Neurology and Clinical Neurophysiology, Amsterdam University Medical Centers, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, The Netherlands
Iwaki, Hirotaka ; Department of Health and Human Services, Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes on Health, Bethesda, Maryland, USA ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA ; Data Tecnica International, Washington, District of Columbia, USA
Gan-Or, Ziv ; Department of Human Genetics, McGill University, Montréal, Canada ; Department of Neurology, The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
International Parkinson's Disease Genomic Consortium
National Institute of Neurological Disorders and Stroke
Subventionnement (détails) :
We thank all participants of the Luxembourg Parkinson's Study for their important support of our research. Data used for the Luxemburg cohort in the preparation of this manuscript were obtained from the National Centre of Excellence in Research on Parkinson's Disease (NCER-PD). We acknowledge the joint effort of the 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 listed below: Geeta Acharya2, Gloria Aguayo2, Myriam Alexandre2, Muhammad Ali1, Wim Ammerlann2, Giuseppe Arena1, Rudi Balling1, Michele Bassis1, Katy Beaumont2, Regina Becker1, Camille Bellora2, Guy Berchem3, Daniela Berg11, Alexandre Bisdorff5, Ibrahim Boussaad1, Kathrin Brockmann11, Jessica Calmes2, Lorieza Castillo2, Gessica Contesotto2, Nico Diederich3, Rene Dondelinger5, Daniela Esteves2, Guy Fagherazzi2, Jean-Yves Ferrand2, Manon Gantenbein2, Thomas Gasser11, Piotr Gawron1, Soumyabrata Ghosh1, Marijus Giraitis2,3, Enrico Glaab1, Elisa Gómez De Lope1, Jérôme Graas2, Mariella Graziano17, Valentin Groues1, Anne Grünewald1, Wei Gu1, Gaël Hammot2, Anne-Marie Hanff2, Linda Hansen1,3, Michael Heneka1, Estelle Henry2, Sylvia Herbrink6, Sascha Herzinger1, Michael Heymann2, Michele Hu8, Alexander Hundt2, Nadine Jacoby18, Jacek Jaroslaw Lebioda1, Yohan Jaroz1, Sonja Jónsdóttir2, Quentin Klopfenstein1, Jochen Klucken1,2,3, Rejko Krüger1,2,3, Pauline Lambert2, Zied Landoulsi1, Roseline Lentz7, Inga Liepelt11, Robert Liszka14, Laura Longhino3, Victoria Lorentz2, Paula Cristina Lupu2, Tainá M. Marques1, Clare Mackay10, Walter Maetzler15, Katrin Marcus13, Guilherme Marques2, Patricia Martins Conde1, Patrick May1, Deborah Mcintyre2, Chouaib Mediouni2, Francoise Meisch1, Myriam Menster2, Maura Minelli2, Michel Mittelbronn1,4, Brit Mollenhauer12, Friedrich Mühlschlegel4, Romain Nati3, Ulf Nehrbass2, Sarah Nickels1, Beatrice Nicolai3, Jean-Paul Nicolay19, Fozia Noor2, Marek Ostaszewski1, Clarissa P. C. Gomes1, Sinthuja Pachchek1, Claire Pauly1,3, Laure Pauly1, Lukas Pavelka1,3, Magali Perquin2, Rosalina Ramos Lima2, Armin Rauschenberger1, Rajesh Rawal1, Dheeraj Reddy Bobbili1, Kirsten Roomp1, Eduardo Rosales2, Isabel Rosety1, Estelle Sandt2, Stefano Sapienza1, Venkata Satagopam1, Margaux Schmitt2, Sabine Schmitz1, Reinhard Schneider1, Jens Schwamborn1, Amir Sharify2, Ekaterina Soboleva1, Kate Sokolowska2, Hermann Thien2, Elodie Thiry3, Rebecca Ting Jiin Loo1, Christophe Trefois1, Johanna Trouet2, Olena Tsurkalenko2, Michel Vaillant2, Mesele Valenti2, Gilles Van Cutsem1,3, Carlos Vega1, Liliana Vilas Boas3, Maharshi Vyas1, Richard Wade-Martins9, Paul Wilmes1, Evi Wollscheid-Lengeling1, Gelani Zelimkhanov3.
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