[en] [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: 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 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 1,612 PD patients with and 3,175 without LID.
RESULTS: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants with reduced time to LID onset (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.
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 :
Neurology Genetics & genetic processes
Author, co-author :
Sosero, Yuri L; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
Bandres-Ciga, Sara; 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, MD, USA
Ferwerda, Bart; Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Tocino, Maria T P; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Belloso, Dìaz R; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Gómez-Garre, Pilar; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; 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 ; CREST, ENSAI, Campus de Ker-Lann, 51 Rue Blaise Pascal - BP 37203 35172 Bruz Cedex, France
Taba, Pille; Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
PAVELKA, Lukas ; University of Luxembourg ; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg ; 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 (LCSB) > Translational Neuroscience
KOLODKIN, Alexey ; University of Luxembourg ; 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 ; 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
van Hilten, Jacobus J; Department of Neurology, Leiden University Medical Center, Leiden
Simon, David K; Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School
Eberly, Shirley; Department of Biostatistics and Computational Biology at the University of Rochester School of Medicine and Dentistry
Alvarez, Ignacio; Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain
Krohn, Lynne; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
Yu, Eric ; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
Freeman, Kathryn ; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
Rudakou, Uladzislau ; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
Ruskey, Jennifer A; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
Asayesh, Farnaz; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
Menéndez-Gonzàlez, Manuel; Facultad de Medicina y Ciencias de la Salud, Universidad de Oviedo, Calle Julián Clavería s/n, 33006 Oviedo, Spain ; Department of Neurology, Hospital Universitario Central de Asturias, Avenida Roma s/n, 33011 Oviedo, Spain ; Instituto de Investigación Sanitaria del Principado de Asturias, Avenida Roma s/n, 33011 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), Strassen, Luxembourg ; Transversal Translational Medicine > Luxembourg Institute of Health (LIH), Strassen, Luxembourg
Corvol, Jean-Christophe; CREST, ENSAI, Campus de Ker-Lann, 51 Rue Blaise Pascal - BP 37203 35172 Bruz Cedex, France
Koks, Sulev ; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Australia ; Perron Institute for Neurological and Translational Science, Nedlands, Australia
Mir, Pablo ; Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain ; 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; 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, MD, USA ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA ; Data Tecnica International, Washington, District of Columbia, USA
Gan-Or, Ziv; Department of Human Genetics, McGill University, Montréal, QC, Canada ; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada ; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
