Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.
GBA1
LRRK2
Parkinson's disease
dopamine
levodopa‐induced dyskinesia
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
12 Aug 2024
12 Aug 2024
Historique:
revised:
10
07
2024
received:
20
09
2023
accepted:
15
07
2024
medline:
12
8
2024
pubmed:
12
8
2024
entrez:
12
8
2024
Statut:
aheadofprint
Résumé
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 (OR 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
Our goal was to investigate the effects of genetic variants on risk and time to LID.
METHODS
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
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 (OR
CONCLUSIONS
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : 5U01NS050095-05
Pays : United States
Investigateurs
Geeta Acharya
(G)
Gloria Aguayo
(G)
Myriam Alexandre
(M)
Muhammad Ali
(M)
Wim Ammerlann
(W)
Giuseppe Arena
(G)
Rudi Balling
(R)
Michele Bassis
(M)
Katy Beaumont
(K)
Regina Becker
(R)
Camille Bellora
(C)
Guy Berchem
(G)
Daniela Berg
(D)
Alexandre Bisdorff
(A)
Ibrahim Boussaad
(I)
Kathrin Brockmann
(K)
Jessica Calme
(J)
Lorieza Castillo
(L)
Gessica Contesotto
(G)
Nico Diederich
(N)
Rene Dondelinger
(R)
Daniela Esteves
(D)
Guy Fagherazzi
(G)
Jean-Yves Ferrand
(JY)
Manon Gantenbein
(M)
Thomas Gasser
(T)
Piotr Gawron
(P)
Soumyabrata Ghosh
(S)
Marijus Giraitis
(M)
Enrico Glaab
(E)
Elisa Gómez De Lope
(EG)
Jérôme Graas
(J)
Mariella Graziano
(M)
Valentin Groues
(V)
Anne Grünewald
(A)
Wei Gu
(W)
Gaël Hammot
(G)
Anne-Marie Hanff
(AM)
Linda Hansen
(L)
Michael Heneka
(M)
Estelle Henr
(E)
Sylvia Herbrink
(S)
Sascha Herzinger
(S)
Michael Heymann
(M)
Michele Hu
(M)
Alexander Hundt
(A)
Nadine Jacoby
(N)
Jacek Jaroslaw Lebioda
(JJ)
Yohan Jaroz
(Y)
Sonja Jónsdóttir
(S)
Quentin Klopfenstein
(Q)
Jochen Klucken
(J)
Rejko Krüger
(R)
Pauline Lambert
(P)
Zied Landoulsi
(Z)
Roseline Lentz
(R)
Inga Liepelt
(I)
Robert Liszka
(R)
Laura Longhino
(L)
Victoria Lorentz
(V)
Paula Cristina Lupu
(PC)
Tainá M Marques
(TM)
Clare Mackay
(C)
Walter Maetzler
(W)
Katrin Marcus
(K)
Guilherme Marques
(G)
Patricia Martins Conde
(PM)
Patrick May
(P)
Deborah Mcintyre
(D)
Chouaib Mediouni
(C)
Francoise Meisch
(F)
Myriam Menster
(M)
Maura Minelli
(M)
Michel Mittelbronn
(M)
Brit Mollenhauer
(B)
Friedrich Mühlschlegel
(F)
Romain Nati
(R)
Ulf Nehrbass
(U)
Sarah Nickels
(S)
Beatrice Nicolai
(B)
Jean-Paul Nicolay
(JP)
Fozia Noor
(F)
Marek Ostaszewski
(M)
Clarissa P C Gomes
(CPC)
Sinthuja Pachchek
(S)
Claire Pauly
(C)
Laure Pauly
(L)
Lukas Pavelka
(L)
Magali Perquin
(M)
Rosalina Ramos Lima
(RR)
Armin Rauschenberger
(A)
Rajesh Rawal
(R)
Dheeraj Reddy Bobbili
(DR)
Kirsten Roomp
(K)
Eduardo Rosales
(E)
Isabel Rosety
(I)
Estelle Sandt
(E)
Stefano Sapienza
(S)
Venkata Satagopam
(V)
Margaux Schmitt
(M)
Sabine Schmitz
(S)
Reinhard Schneide
(R)
Jens Schwamborn
(J)
Amir Sharify
(A)
Ekaterina Soboleva
(E)
Kate Sokolowska
(K)
Hermann Thien
(H)
Elodie Thiry
(E)
Rebecca Ting Jiin Loo
(RTJ)
Christophe Trefois
(C)
Johanna Trouet
(J)
Olena Tsurkalenko
(O)
Michel Vaillant
(M)
Mesele Valenti
(M)
Gilles Van Cutsem
(G)
Carlos Vega
(C)
Liliana Vilas Boas
(LV)
Maharshi Vyas
(M)
Richard Wade-Martins
(R)
Paul Wilmes
(P)
Evi Wollscheid-Lengeling
(E)
Gelani Zelimkhanov
(G)
Informations de copyright
© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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