Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.
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Sosero Yuri L, Bandres-Ciga Sara, Ferwerda Bart, Tocino Maria T P, Belloso Dìaz R, Gómez-Garre Pilar, Faouzi Johann, Taba Pille, Pavelka Lukas, Marques Tainà M, Gomes Clarissa P C, Kolodkin Alexey, May Patrick, Milanowski Lukasz M, Wszolek Zbigniew K, Uitti Ryan J, Heutink Peter, van Hilten Jacobus J, Simon David K, Eberly Shirley, Alvarez Ignacio, Krohn Lynne, Yu Eric, Freeman Kathryn, Rudakou Uladzislau, Ruskey Jennifer A, Asayesh Farnaz, Menéndez-Gonzàlez Manuel, Pastor Pau, Ross Owen A, Krüger Rejko, NCER‐PD Consortium, Corvol Jean-Christophe, Koks Sulev, Mir Pablo, De Bie Rob M A, Iwaki Hirotaka, Gan-Or Ziv, International Parkinson's Disease Genomic Consortium
Аннотация
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.