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

Levodopa-induced dyskinesia (LID) is a frequent adverse effect of levodopa, a primary treatment for motor symptoms in Parkinson’s disease (PD). Prior studies suggest that LID is linked to disruption of the dopaminergic system and PD-related genes, including GBA1 and LRRK2. We investigated the effects of genetic variants on LID risk and time to onset.

We conducted a genome-wide association study, analyses of GBA1 and LRRK2 variants, and calculated polygenic risk scores (PRS) based on PD risk variants and dopaminergic pathway genes. Logistic regression assessed LID risk, and Cox regression evaluated time to LID onset in 1612 PD patients with LID and 3175 without.

GBA1 variants were associated with increased LID risk (OR = 1.65; 95% CI, 1.21–2.26; P = 0.0017), while LRRK2 variants were linked to shorter time to LID onset (HR = 1.42; 95% CI, 1.09–1.84; P = 0.0098). Individuals in the highest quartile of the PD PRS had increased LID risk (OR = 1.27; 95% CI, 1.03–1.56; P = 0.0210). Higher dopaminergic pathway PRS quartiles were associated with reduced time to LID development (third quartile HR = 1.38; P = 0.0128; fourth quartile HR = 1.38; P = 0.0147).

These findings indicate that genetic variants associated with PD and dopaminergic signaling influence both the risk and timing of LID, warranting further investigation into their clinical relevance.

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