Dopamine pathway and Parkinson’s risk variants are associated with levodopa-induced dyskinesia

Abstract

AbstractBackgroundLevodopa-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, includingGBA1andLRRK2.ObjectivesTo investigate the effects of genetic variants on risk and time to LID.MethodsWe performed a genome-wide association study (GWAS) and analyses focused onGBA1andLRRK2variants. 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.ResultsWe found thatGBA1variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) andLRRK2variants 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 (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).ConclusionsThis 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.