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000272822 0247_ $$2doi$$a10.1002/mds.29960
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000272822 037__ $$aDZNE-2024-01240
000272822 041__ $$aEnglish
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000272822 1001_ $$aSosero, Yuri L$$b0
000272822 245__ $$aDopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.
000272822 260__ $$aNew York, NY$$bWiley$$c2024
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000272822 520__ $$aLevodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.Our goal was to investigate the effects of genetic variants on risk and time to LID.We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID.We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147).This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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000272822 650_7 $$2Other$$aGBA1
000272822 650_7 $$2Other$$aLRRK2
000272822 650_7 $$2Other$$aParkinson's disease
000272822 650_7 $$2Other$$adopamine
000272822 650_7 $$2Other$$alevodopa‐induced dyskinesia
000272822 650_7 $$046627O600J$$2NLM Chemicals$$aLevodopa
000272822 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000272822 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGlucosylceramidase
000272822 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLRRK2 protein, human
000272822 650_7 $$0VTD58H1Z2X$$2NLM Chemicals$$aDopamine
000272822 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGBA protein, human
000272822 650_7 $$2NLM Chemicals$$aAntiparkinson Agents
000272822 650_2 $$2MeSH$$aHumans
000272822 650_2 $$2MeSH$$aLevodopa: adverse effects
000272822 650_2 $$2MeSH$$aParkinson Disease: genetics
000272822 650_2 $$2MeSH$$aParkinson Disease: drug therapy
000272822 650_2 $$2MeSH$$aDyskinesia, Drug-Induced: genetics
000272822 650_2 $$2MeSH$$aMale
000272822 650_2 $$2MeSH$$aFemale
000272822 650_2 $$2MeSH$$aAged
000272822 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000272822 650_2 $$2MeSH$$aGlucosylceramidase: genetics
000272822 650_2 $$2MeSH$$aMiddle Aged
000272822 650_2 $$2MeSH$$aGenome-Wide Association Study
000272822 650_2 $$2MeSH$$aDopamine: metabolism
000272822 650_2 $$2MeSH$$aAntiparkinson Agents: adverse effects
000272822 650_2 $$2MeSH$$aGenetic Predisposition to Disease: genetics
000272822 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide: genetics
000272822 7001_ $$00000-0003-0056-1361$$aBandres-Ciga, Sara$$b1
000272822 7001_ $$aFerwerda, Bart$$b2
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000272822 7001_ $$aRuskey, Jennifer A$$b25
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000272822 7001_ $$00000-0003-4813-756X$$aRoss, Owen A$$b29
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000272822 7001_ $$aConsortium, NCER-PD$$b31$$eCollaboration Author
000272822 7001_ $$00000-0001-7325-0199$$aCorvol, Jean-Christophe$$b32
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000272822 7001_ $$00000-0003-0332-234X$$aGan-Or, Ziv$$b37
000272822 7001_ $$aConsortium, International Parkinson's Disease Genomic$$b38$$eCollaboration Author
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