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. 2024 Oct;39(10):1773-1783.
doi: 10.1002/mds.29960. Epub 2024 Aug 12.

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

Yuri L Sosero  1   2 , Sara Bandres-Ciga  3 , Bart Ferwerda  4 , Maria T P Tocino  5   6 , Dìaz R Belloso  5   6 , Pilar Gómez-Garre  5   6 , Johann Faouzi  7   8 , Pille Taba  9 , Lukas Pavelka  10   11 , Tainà M Marques  10 , Clarissa P C Gomes  12 , Alexey Kolodkin  10 , Patrick May  10   11 , Lukasz M Milanowski  13   14 , Zbigniew K Wszolek  14 , Ryan J Uitti  14 , Peter Heutink  15 , Jacobus J van Hilten  16 , David K Simon  17 , Shirley Eberly  18 , Ignacio Alvarez  19 , Lynne Krohn  1   2 , Eric Yu  1   2 , Kathryn Freeman  1   2 , Uladzislau Rudakou  1   2 , Jennifer A Ruskey  2   20 , Farnaz Asayesh  2   20 , Manuel Menéndez-Gonzàlez  21   22   23 , Pau Pastor  19   24 , Owen A Ross  14 , Rejko Krüger  10   11   12 ; NCER‐PD Consortium; Jean-Christophe Corvol  8 , Sulev Koks  25   26 , Pablo Mir  5   6   27 , Rob M A De Bie  28 , Hirotaka Iwaki  3   29   30 , Ziv Gan-Or  1   2   20 ; International Parkinson's Disease Genomic Consortium
Collaborators, Affiliations

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

Yuri L Sosero et al. Mov Disord. 2024 Oct.

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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: GBA1; LRRK2; Parkinson's disease; dopamine; levodopa‐induced dyskinesia.

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Conflict of interest statement

ZGO has received consulting fees from Lysosomal Therapeutics Inc., Idorsia, Prevail Therapeutics, Denali, Ono Therapeutics, Neuron23, Handl Therapeutics, UBC, Bial Biotech Inc., Bial, Deerfield, Guidepoint, Lighthouse and VanquaBio. None of these companies were involved in any parts of preparing, drafting and publishing this study. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206) and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Cfthsf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company.

Figures

Fig. 1
Fig. 1. A-B – Association between GBA1 variants and LID
The meta-analysis forest plot shows the coefficient (black squares) and 95% confidence interval (bars) of the analyses in each single cohort. The size of the square is proportional to the weight the cohort had on the overall meta-analysis, based on their single standard error. The black diamond at the bottom represents the overall coefficient and confidence interval. A. Logistic regression between GBA1 variants and LID risk; B. Cox regression between GBA1 variants and time to development of LID. FE: fixed effect model; AMP-PD: Accelerating Medicines Partnership Parkinson's disease, including the New Discovery of Biomarkers (BioFIND), the Harvard Biomarker Study (HBS) and the Parkinson’s Disease Biomarkers Program (PDBP) cohorts; Barcelona: Hospital Universitari Mutua de Terrassa, Spain; CORIELL: NINDS Exploratory Trials in PD Long-Term Study 1 (NET-PD LS1), Coriell Institute for Medical Research, USA; DIGPD: Drug Interaction With Genes in Parkinson's Disease, France; LEAP: Levodopa in Early Parkinson's Disease, Netherlands; Luxemburg: Luxembourg Centre for Systems Biomedicine; Mayo: Mayo Clinic, USA; McGill: McGill University, Canada; Oviedo: Central University Hospital of Asturias, Spain; PreCEPT: Parkinson Research Examination of CEP-1347 Trial; SCOPA: SCales for Outcomes in PArkinson's disease; Sevilla: Universidad de Sevilla; Tartu: University of Tartu
Fig. 2
Fig. 2. A-B - Association between LRRK2 variants and LID
A. Logistic regression between LRRK2 variants and LID risk; B. Cox regression between LRRK2 variants and time to development of LID.
Fig- 3
Fig- 3. A-B - Logistic regression between PRS aggregating PD risk variants and LID risk
A. The plot shows the association between each PRS quartile and LID risk compared with the first quartile, meta-analyzing the results across the cohorts. The Y axis represents the PRS quartile, the X axis the odds ratio (red dot) and 95% confidence interval (red bar). The presence of an asterisk indicates a significant association (p<0.05). B. The forest plot shows the association between PRS as a continuous variable and LID risk. CI: confidence interval.
Fig. 4
Fig. 4. A-B - Cox regression between the dopaminergic transmission pathway PES and time to development of LID
A. The plot shows the association between each PES quartile and time to development of LID compared with the first quartile, meta-analyzing the results across the cohorts. The Y axis represents the PRS quartile, the X axis the hazard ratio (red dot) and 95% confidence interval (red bar). B. The forest plot shows the association between PES as a continuous variable and time to development of LID.
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