Citations 2
Rare but Relevant? Assessing Variants in Dystonia‐Linked Genes in Parkinson's Disease
Screven, Laurel A. , Tan, Ai Huey , Fenn, Matilda, Frost, Joshua L.I., Jankovic, Joseph, Jasaityte, Simona , Jeon, Beomseok , Sarmiento, Ignacio Juan Keller , Krüger, Rejko , Kuhlenbäumer, Gregor , Schirinzi, Tommaso , Shulman, Joshua M., Uitti, Ryan J. , Wu, Lesley , Zeuner, Kirsten E., Blauwendraat, Cornelis , Singleton, Andrew, Lohmann, Katja , (GP2), the Global Parkinson's Genetics Program, Tan, Ai Huey , Jeon, Beom Seok , Lin, Chin-Hsien , Schirinzi, Tommaso , Shin, Jung Hwan , Tay, Yi Wen , Uitti, Ryan, Warner, Thomas T. , Wszolek, Z.K. , Wu, Ruey-Meei , Blauwendraat, Cornelis , Morris, Huw R , Lohmann, Katja , Lange, Lara Mariah , Fang, Zih‐Hua , Alcalay, Roy N. , Amouri, Rim , Bovenzi, Roberta , Frost, Joshua L.I., Jankovic, Joseph J. , Jaunmuktane, Zane , Lin, Chin‐Hsien , Pavelka, Lukas , Periñán, María Teresa , Sassi, Samia Ben , Shulman, Joshua M. , Wszołek, Zbigniew K. , Wu, Ruey‐Meei , Singleton, Andrew , Mencacci, Niccolò Emanuele , Morris, Huw R. , Lim, Shen‐Yang , Klein, Christine , (GP2), the Global Parkinson's Genetics Program
Movement Disorders | October 11, 2025 | Volume: 41 | Issue: 1 | Pages: 247-259
Abstract Background Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective The aim was to assess the frequency of dystonia‐linked pathogenic variants in PD. Methods We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership‐Parkinson's Disease (AMP‐PD) for variants in genes linked to isolated dystonia, dystonia‐parkinsonism, and myoclonus‐dystonia. Results Pathogenic variants were identified only in PD patients. Forty‐five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia‐linked genes, most frequently in GCH1 , followed by VPS16 . Conclusion Though rare, pathogenic variants in dystonia‐linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD‐relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa‐Induced Dyskinesia
Sosero, Yuri L. , Bandrés‐Ciga, Sara , Tocino, Maria Teresa Periñan, Belloso, Dìaz R., Gómez‐Garre, Pilar , Faouzi, Johann , Pavelka, Lukas , Marques, Tainá M. , May, Patrick , Milanowski, Łukasz , Uitti, Ryan J. , Hilten, Jacobus J. van , Simon, David K. , Eberly, Shirley , Krohn, Lynne , Freeman, Kathryn , Ruskey, Jennifer A. , Asayesh, Farnaz , Menéndez‐González, Manuel , Pástor, Pau , Ross, Owen A. , Krüger, Rejko , Kõks, Sulev, Mir, Pablo , Klucken, Jochen , Gómez‐Garre, Pilar , Fatima, Noor , Gómez-Garre, Pilar , May, Patrick , Milanowski, Łukasz M , Wszolek, Z.K. , Simon, David K , Ross, Owen A , Corvol, Jean-Christophe , Koks, Sulev , Mir, Pablo , de Bie, Rob M A , Iwaki, Hirotaka , Gan-Or, Ziv , Pastor, Pau , Ferwerda, Bart , Taba, Pille , Gomes, Clarissa P. C. , Kolodkin, Alexey N. , Wszołek, Zbigniew K. , Heutink, Peter , Álvarez, Ignacio , Yu, Eric , Freeman, Kathryn, Rudakou, Uladzislau , Corvol, Jean‐Christophe , Bie, Rob M.A. de , Gan‐Or, Ziv
Movement Disorders | August 12, 2024 | Volume: 39 | Issue: 10 | Pages: 1773-1783
Abstract 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 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 (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. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.