TY - UNPB
T1 - Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia
AU - Sosero, Yuri L
AU - Bandres-Ciga, Sara
AU - Ferwerda, Bart
AU - Tocino, Maria T P
AU - Belloso, Dìaz R
AU - Gómez-Garre, Pilar
AU - Faouzi, Johann
AU - Taba, Pille
AU - Pavelka, Lukas
AU - Marques, Tainà M
AU - Gomes, Clarissa P C
AU - Kolodkin, Alexey
AU - May, Patrick
AU - Milanowski, Lukasz M
AU - Wszolek, Zbigniew K
AU - Uitti, Ryan J
AU - Heutink, Peter
AU - van Hilten, Jacobus J
AU - Simon, David K
AU - Eberly, Shirley
AU - Alvarez, Ignacio
AU - Krohn, Lynne
AU - Yu, Eric
AU - Freeman, Kathryn
AU - Rudakou, Uladzislau
AU - Ruskey, Jennifer A
AU - Asayesh, Farnaz
AU - Menéndez-Gonzàlez, Manuel
AU - Pastor, Pau
AU - Ross, Owen A
AU - Krüger, Rejko
AU - Corvol, Jean-Christophe
AU - Koks, Sulev
AU - Mir, Pablo
AU - De Bie, Rob M A
AU - Iwaki, Hirotaka
AU - Gan-Or, Ziv
PY - 2023/9/20
Y1 - 2023/9/20
N2 - 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: 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 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 1,612 PD patients with and 3,175 without LID.
RESULTS: We found that
GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and
LRRK2 variants with reduced time to LID onset (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
fourth_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 (HR
third_quartile= 1.38, 95% CI=1.07-1.79,
p= 0.0128; HR
fourth_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.
AB - 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: 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 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 1,612 PD patients with and 3,175 without LID.
RESULTS: We found that
GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and
LRRK2 variants with reduced time to LID onset (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
fourth_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 (HR
third_quartile= 1.38, 95% CI=1.07-1.79,
p= 0.0128; HR
fourth_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.
U2 - 10.1101/2023.08.28.23294610
DO - 10.1101/2023.08.28.23294610
M3 - Preprint
C2 - 37790572
T3 - medRxiv : the preprint server for health sciences
BT - Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia
ER -