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

Yuri L Sosero; Sara Bandres-Ciga; Bart Ferwerda; Maria T P Tocino; Dìaz R Belloso; Pilar Gómez-Garre; Johann Faouzi; Pille Taba; Lukas Pavelka; Tainà M Marques; Clarissa P C Gomes; Alexey Kolodkin; Patrick May; Lukasz M Milanowski; Zbigniew K Wszolek; Ryan J Uitti; Peter Heutink; Jacobus J van Hilten; David K Simon; Shirley Eberly; Ignacio Alvarez; Lynne Krohn; Eric Yu; Kathryn Freeman; Uladzislau Rudakou; Jennifer A Ruskey; Farnaz Asayesh; Manuel Menéndez-Gonzàlez; Pau Pastor; Owen A Ross; Rejko Krüger; Jean-Christophe Corvol; Sulev Koks; Pablo Mir; Rob M A De Bie; Hirotaka Iwaki; Ziv Gan-Or

doi:10.1101/2023.08.28.23294610

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

Yuri L Sosero, Sara Bandres-Ciga, Bart Ferwerda, Maria T P Tocino, Dìaz R Belloso, Pilar Gómez-Garre, Johann Faouzi, Pille Taba, Lukas Pavelka, Tainà M Marques, Clarissa P C Gomes, Alexey Kolodkin, Patrick May, Lukasz M Milanowski, Zbigniew K Wszolek, Ryan J Uitti, Peter Heutink, Jacobus J van Hilten, David K Simon, Shirley EberlyIgnacio Alvarez, Lynne Krohn, Eric Yu, Kathryn Freeman, Uladzislau Rudakou, Jennifer A Ruskey, Farnaz Asayesh, Manuel Menéndez-Gonzàlez, Pau Pastor, Owen A Ross, Rejko Krüger, Jean-Christophe Corvol, Sulev Koks, Pablo Mir, Rob M A De Bie, Hirotaka Iwaki, Ziv Gan-Or^*

^*Corresponding author for this work

Transversal Translational Medicine

Research output: Working paper › Preprint

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: 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.

Original language	English
DOIs	https://doi.org/10.1101/2023.08.28.23294610
Publication status	Published - 20 Sept 2023

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Name	medRxiv : the preprint server for health sciences

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Sosero, Y. L., Bandres-Ciga, S., Ferwerda, B., Tocino, M. T. P., Belloso, D. R., Gómez-Garre, P., Faouzi, J., Taba, P., Pavelka, L., Marques, T. M., Gomes, C. P. C., Kolodkin, A., May, P., Milanowski, L. M., Wszolek, Z. K., Uitti, R. J., Heutink, P., van Hilten, J. J., Simon, D. K., ... Gan-Or, Z. (2023). Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia. (medRxiv : the preprint server for health sciences). https://doi.org/10.1101/2023.08.28.23294610

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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: 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.",

author = "Sosero, {Yuri L} and Sara Bandres-Ciga and Bart Ferwerda and Tocino, {Maria T P} and Belloso, {D{\`i}az R} and Pilar G{\'o}mez-Garre and Johann Faouzi and Pille Taba and Lukas Pavelka and Marques, {Tain{\`a} M} and Gomes, {Clarissa P C} and Alexey Kolodkin and Patrick May and Milanowski, {Lukasz M} and Wszolek, {Zbigniew K} and Uitti, {Ryan J} and Peter Heutink and {van Hilten}, {Jacobus J} and Simon, {David K} and Shirley Eberly and Ignacio Alvarez and Lynne Krohn and Eric Yu and Kathryn Freeman and Uladzislau Rudakou and Ruskey, {Jennifer A} and Farnaz Asayesh and Manuel Men{\'e}ndez-Gonz{\`a}lez and Pau Pastor and Ross, {Owen A} and Rejko Kr{\"u}ger and Jean-Christophe Corvol and Sulev Koks and Pablo Mir and {De Bie}, {Rob M A} and Hirotaka Iwaki and Ziv Gan-Or",

year = "2023",

month = sep,

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doi = "10.1101/2023.08.28.23294610",

language = "English",

series = "medRxiv : the preprint server for health sciences",

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Sosero, YL, Bandres-Ciga, S, Ferwerda, B, Tocino, MTP, Belloso, DR, Gómez-Garre, P, Faouzi, J, Taba, P, Pavelka, L, Marques, TM, Gomes, CPC, Kolodkin, A, May, P, Milanowski, LM, Wszolek, ZK, Uitti, RJ, Heutink, P, van Hilten, JJ, Simon, DK, Eberly, S, Alvarez, I, Krohn, L, Yu, E, Freeman, K, Rudakou, U, Ruskey, JA, Asayesh, F, Menéndez-Gonzàlez, M, Pastor, P, Ross, OA, Krüger, R, Corvol, J-C, Koks, S, Mir, P, De Bie, RMA, Iwaki, H & Gan-Or, Z 2023 'Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia' medRxiv : the preprint server for health sciences. https://doi.org/10.1101/2023.08.28.23294610

TY - UNPB

T1 - Dopamine pathway and Parkinson's risk variants are associated with levodopa-induced dyskinesia

AU - Sosero, Yuri L

AU - Bandres-Ciga, Sara

AU - Ferwerda, Bart

AU - Tocino, Maria T P

AU - Belloso, Dìaz R

AU - Gómez-Garre, Pilar

AU - Faouzi, Johann

AU - Taba, Pille

AU - Pavelka, Lukas

AU - Marques, Tainà M

AU - Gomes, Clarissa P C

AU - Kolodkin, Alexey

AU - May, Patrick

AU - Milanowski, Lukasz M

AU - Wszolek, Zbigniew K

AU - Uitti, Ryan J

AU - Heutink, Peter

AU - van Hilten, Jacobus J

AU - Simon, David K

AU - Eberly, Shirley

AU - Alvarez, Ignacio

AU - Krohn, Lynne

AU - Yu, Eric

AU - Freeman, Kathryn

AU - Rudakou, Uladzislau

AU - Ruskey, Jennifer A

AU - Asayesh, Farnaz

AU - Menéndez-Gonzàlez, Manuel

AU - Pastor, Pau

AU - Ross, Owen A

AU - Krüger, Rejko

AU - Corvol, Jean-Christophe

AU - Koks, Sulev

AU - Mir, Pablo

AU - De Bie, Rob M A

AU - Iwaki, Hirotaka

AU - Gan-Or, Ziv

PY - 2023/9/20

Y1 - 2023/9/20

N2 - 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.

AB - 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.

U2 - 10.1101/2023.08.28.23294610

DO - 10.1101/2023.08.28.23294610

M3 - Preprint

C2 - 37790572

T3 - medRxiv : the preprint server for health sciences

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

ER -

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

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