Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia

Lukas Pavelka, Alexey Kolodkin, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Katy Beaumont, Camille Bellora, Guy Berchem, Ibrahim Boussaad, Gessica Contesotto, Daniela Esteves, Guy Fagherazzi, Jean Yves Ferrand, Manon Gantenbein, Marijus Giraitis, Jérôme Graas, Michael Heymann, Alexander Hundt, Sonja Jónsdóttir, Jochen KluckenPauline Lambert, Zied Landoulsi, Victoria Lorentz, Paula Cristina Lupu, Tainá M. Marques, Guilherme Marques, Deborah Mcintyre, Chouaib Mediouni, Myriam Menster, Michel Mittelbronn, Ulf Nehrbass, Sarah Nickels, Fozia Noor, Marek Ostaszewski, Claire Pauly, Laure Pauly, Lukas Pavelka, Magali Perquin, Rosalina Ramos Lima, Armin Rauschenberger, Estelle Sandt, Stefano Sapienza, Margaux Schmitt, Amir Sharify, Kate Sokolowska, Hermann Thien, Johanna Trouet, Olena Tsurkalenko, Michel Vaillant, Mesele Valenti, Carlos Vega, Gelani Zelimkhanov, Wim Ammerlaan, the NCER-PD Consortium, the International Parkinson's Disease Genomic Consortium, Ziv Gan-Or*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalMovement Disorders
Early online date12 Aug 2024
DOIs
Publication statusE-pub ahead of print - 12 Aug 2024

Keywords

  • GBA1
  • LRRK2
  • Parkinson's disease
  • dopamine
  • levodopa-induced dyskinesia

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