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Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543218/ https://www.ncbi.nlm.nih.gov/pubmed/37790572 http://dx.doi.org/10.1101/2023.08.28.23294610 |
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author | 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 Corvol, Jean-Christophe Koks, Sulev Mir, Pablo De Bie, Rob M.A. Iwaki, Hirotaka Gan-Or, Ziv |
author_facet | 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 Corvol, Jean-Christophe Koks, Sulev Mir, Pablo De Bie, Rob M.A. Iwaki, Hirotaka Gan-Or, Ziv |
author_sort | Sosero, Yuri L. |
collection | PubMed |
description | 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: 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 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. RESULTS: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants 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 (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. |
format | Online Article Text |
id | pubmed-10543218 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-105432182023-10-03 Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia 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 Corvol, Jean-Christophe Koks, Sulev Mir, Pablo De Bie, Rob M.A. Iwaki, Hirotaka Gan-Or, Ziv medRxiv Article 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: 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 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. RESULTS: We found that GBA1 variants were associated with LID risk (OR=1.65, 95% CI=1.21-2.26, p=0.0017) and LRRK2 variants 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 (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. Cold Spring Harbor Laboratory 2023-09-20 /pmc/articles/PMC10543218/ /pubmed/37790572 http://dx.doi.org/10.1101/2023.08.28.23294610 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article 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 Corvol, Jean-Christophe Koks, Sulev Mir, Pablo De Bie, Rob M.A. Iwaki, Hirotaka Gan-Or, Ziv Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title | Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title_full | Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title_fullStr | Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title_full_unstemmed | Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title_short | Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia |
title_sort | dopamine pathway and parkinson's risk variants are associated with levodopa-induced dyskinesia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543218/ https://www.ncbi.nlm.nih.gov/pubmed/37790572 http://dx.doi.org/10.1101/2023.08.28.23294610 |
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