Journal Article

DZNE-2024-01240

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

Sosero, Y. L. ; Bandres-Ciga, S. ; Ferwerda, B. ; Tocino, M. T. P. ; Belloso, D. R. ; Gómez-Garre, P. ; Faouzi, J. ; Taba, P. ; Pavelka, L. ; Marques, T. M. ; Gomes, C. P. C. ; Kolodkin, A. ; May, P. ; Milanowski, L. M. ; Wszolek, Z. K. ; Uitti, R. J. ; Heutink, P.DZNE* ; van Hilten, J. J. ; Simon, D. K. ; Eberly, S. ; Alvarez, I. ; Krohn, L. ; Yu, E. ; Freeman, K. ; Rudakou, U. ; Ruskey, J. A. ; Asayesh, F. ; Menéndez-Gonzàlez, M. ; Pastor, P. ; Ross, O. A. ; Krüger, R. ; Consortium, N.-P. (Collaboration Author) ; Corvol, J.-C. ; Koks, S. ; Mir, P. ; De Bie, R. M. A. ; Iwaki, H. ; Gan-Or, Z. ; Consortium, I. P. D. G. (Collaboration Author) ; Acharya, G. (Contributor) ; Aguayo, G. (Contributor) ; Alexandre, M. (Contributor) ; Ali, M. (Contributor) ; Ammerlann, W. (Contributor) ; Arena, G. (Contributor) ; Balling, R. (Contributor) ; Bassis, M. (Contributor) ; Beaumont, K. (Contributor) ; Becker, R. (Contributor) ; Bellora, C. (Contributor) ; Berchem, G. (Contributor) ; Berg, D. (Contributor) ; Bisdorff, A. (Contributor) ; Boussaad, I. (Contributor) ; Brockmann, K. (Contributor)Extern* ; Calme, J. (Contributor) ; Castillo, L. (Contributor) ; Contesotto, G. (Contributor) ; Diederich, N. (Contributor) ; Dondelinger, R. (Contributor) ; Esteves, D. (Contributor) ; Fagherazzi, G. (Contributor) ; Ferrand, J.-Y. (Contributor) ; Gantenbein, M. (Contributor) ; Gasser, T. (Contributor)Extern* ; Gawron, P. (Contributor) ; Ghosh, S. (Contributor) ; Giraitis, M. (Contributor) ; Glaab, E. (Contributor) ; De Lope, E. G. (Contributor) ; Graas, J. (Contributor) ; Graziano, M. (Contributor) ; Groues, V. (Contributor) ; Grünewald, A. (Contributor) ; Gu, W. (Contributor) ; Hammot, G. (Contributor) ; Hanff, A.-M. (Contributor) ; Hansen, L. (Contributor) ; Heneka, M. (Contributor)Extern* ; Henr, E. (Contributor) ; Herbrink, S. (Contributor) ; Herzinger, S. (Contributor) ; Heymann, M. (Contributor) ; Hu, M. (Contributor) ; Hundt, A. (Contributor) ; Jacoby, N. (Contributor) ; Lebioda, J. J. (Contributor) ; Jaroz, Y. (Contributor) ; Jónsdóttir, S. (Contributor) ; Klopfenstein, Q. (Contributor) ; Klucken, J. (Contributor) ; Krüger, R. (Contributor) ; Lambert, P. (Contributor) ; Landoulsi, Z. (Contributor) ; Lentz, R. (Contributor) ; Liepelt-Scarfone, I. (Contributor)Extern* ; Liszka, R. (Contributor) ; Longhino, L. (Contributor) ; Lorentz, V. (Contributor) ; Lupu, P. C. (Contributor) ; Marques, T. M. (Contributor) ; Mackay, C. (Contributor) ; Maetzler, W. (Contributor) ; Marcus, K. (Contributor) ; Marques, G. (Contributor) ; Conde, P. M. (Contributor) ; May, P. (Contributor) ; Mcintyre, D. (Contributor) ; Mediouni, C. (Contributor) ; Meisch, F. (Contributor) ; Menster, M. (Contributor) ; Minelli, M. (Contributor) ; Mittelbronn, M. (Contributor) ; Mollenhauer, B. (Contributor)Extern* ; Mühlschlegel, F. (Contributor) ; Nati, R. (Contributor) ; Nehrbass, U. (Contributor) ; Nickels, S. (Contributor) ; Nicolai, B. (Contributor) ; Nicolay, J.-P. (Contributor) ; Noor, F. (Contributor) ; Ostaszewski, M. (Contributor) ; Gomes, C. P. C. (Contributor) ; Pachchek, S. (Contributor) ; Pauly, C. (Contributor) ; Pauly, L. (Contributor) ; Pavelka, L. (Contributor) ; Perquin, M. (Contributor) ; Lima, R. R. (Contributor) ; Rauschenberger, A. (Contributor) ; Rawal, R. (Contributor) ; Bobbili, D. R. (Contributor) ; Roomp, K. (Contributor) ; Rosales, E. (Contributor) ; Rosety, I. (Contributor) ; Sandt, E. (Contributor) ; Sapienza, S. (Contributor) ; Satagopam, V. (Contributor) ; Schmitt, M. (Contributor) ; Schmitz, S. (Contributor) ; Schneide, R. (Contributor) ; Schwamborn, J. (Contributor) ; Sharify, A. (Contributor) ; Soboleva, E. (Contributor) ; Sokolowska, K. (Contributor) ; Thien, H. (Contributor) ; Thiry, E. (Contributor) ; Loo, R. T. J. (Contributor) ; Trefois, C. (Contributor) ; Trouet, J. (Contributor) ; Tsurkalenko, O. (Contributor) ; Vaillant, M. (Contributor) ; Valenti, M. (Contributor) ; Van Cutsem, G. (Contributor) ; Vega, C. (Contributor) ; Boas, L. V. (Contributor) ; Vyas, M. (Contributor) ; Wade-Martins, R. (Contributor) ; Wilmes, P. (Contributor) ; Wollscheid-Lengeling, E. (Contributor) ; Zelimkhanov, G. (Contributor)

2024
Wiley New York, NY

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Please use a persistent id in citations: doi:10.1002/mds.29960

Abstract: 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.Our goal was to investigate the effects of genetic variants on risk and time to LID.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.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).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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keyword(s): Humans (MeSH) ; Levodopa: adverse effects (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: drug therapy (MeSH) ; Dyskinesia, Drug-Induced: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Glucosylceramidase: genetics (MeSH) ; Middle Aged (MeSH) ; Genome-Wide Association Study (MeSH) ; Dopamine: metabolism (MeSH) ; Antiparkinson Agents: adverse effects (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; GBA1 ; LRRK2 ; Parkinson's disease ; dopamine ; levodopa‐induced dyskinesia ; Levodopa ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Glucosylceramidase ; LRRK2 protein, human ; Dopamine ; GBA protein, human ; Antiparkinson Agents

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2024

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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