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

Yuri L. Sosero; Sara Bandres-Ciga; Bart Ferwerda; Maria T.P. Tocino; Dìaz R. Belloso; Pilar Gómez-Garre; Johann Faouzi; Pille Taba; Lukas Pavelka; Tainà M. Marques; Clarissa P.C. Gomes; Alexey Kolodkin; Patrick May; Lukasz M. Milanowski; Zbigniew K. Wszolek; Ryan J. Uitti; Peter Heutink; Jacobus J. van Hilten; David K. Simon; Shirley Eberly; Ignacio Alvarez; Lynne Krohn; Eric Yu; Kathryn Freeman; Uladzislau Rudakou; Jennifer A. Ruskey; Farnaz Asayesh; Manuel Menéndez-Gonzàlez; Pau Pastor; Owen A. Ross; Rejko Krüger; Jean‐Christophe Corvol; Sulev Koks; Pablo Mir; Rob M.A. De Bie; Hirotaka Iwaki; Ziv Gan-Or; the NCER‐PD Consortium

doi:10.1002/mds.29960

Back

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

Journal article

Open access

Peer reviewed

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

Yuri L. Sosero, Sara Bandres-Ciga, Bart Ferwerda, Maria T.P. Tocino, Dìaz R. Belloso, Pilar Gómez-Garre, Johann Faouzi, Pille Taba, Lukas Pavelka, Tainà M. Marques, …

Movement disorders, Early View

2024

DOI: https://doi.org/10.1002/mds.29960

Files and links (1)

pdf

Published 1.01 MBDownload View

Published (Version of Record)CC BY-NC-ND V4.0, Open Access

Abstract

levodopa-induced dyskinesia

Parkinson’s disease

dopamine

GBA1

LRRK2

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.

Details

Title: Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa‐Induced Dyskinesia
Authors/Creators: Yuri L. Sosero - McGill University
Sara Bandres-Ciga - National Institute of Neurological Disorders and Stroke
Bart Ferwerda - University of Amsterdam
Maria T.P. Tocino - Hospital Universitario Virgen del Rocío
Dìaz R. Belloso - Hospital Universitario Virgen del Rocío
Pilar Gómez-Garre - Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
Johann Faouzi - Centre National de la Recherche Scientifique
Pille Taba - Tartu University Hospital
Lukas Pavelka - Luxembourg Institute of Health
Tainà M. Marques - Luxembourg Institute of Health
Clarissa P.C. Gomes - University of Luxembourg
Alexey Kolodkin - Luxembourg Institute of Health
Patrick May - University of Luxembourg
Lukasz M. Milanowski - Medical University of Warsaw
Zbigniew K. Wszolek - Mayo Clinic in Florida
Ryan J. Uitti - Jacksonville College
Peter Heutink - German Center for Neurodegenerative Diseases
Jacobus J. van Hilten - Leiden University Medical Center
David K. Simon - Beth Israel Deaconess Medical Center
Shirley Eberly - University of Rochester
Ignacio Alvarez - Mútua Terrassa
Lynne Krohn - McGill University
Eric Yu - McGill University
Kathryn Freeman - McGill University
Uladzislau Rudakou - McGill University
Jennifer A. Ruskey - Montreal Neurological Institute and Hospital
Farnaz Asayesh - Montreal Neurological Institute and Hospital
Manuel Menéndez-Gonzàlez - Instituto de Investigación Sanitaria del Principado de Asturias
Pau Pastor - University Hospital Mútua de Terrassa
Owen A. Ross - Jacksonville College
Rejko Krüger - University of Luxembourg
Jean‐Christophe Corvol - ENSAE Paris
Sulev Koks - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
Pablo Mir - Biomedical Research Networking Center on Neurodegenerative Diseases
Rob M.A. De Bie - Amsterdam Neuroscience
Hirotaka Iwaki - Data Tecnica International (United States)
Ziv Gan-Or - McGill University
the NCER‐PD Consortium
Publication Details: Movement disorders, Early View
Publisher: Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Identifiers: 991005692862507891
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Metrics

5 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.67 Parkinson's Disease
Web Of Science research areas: Clinical Neurology
ESI research areas: Neuroscience & Behavior