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

medRxiv [Preprint]. 2023 Sep 20:2023.08.28.23294610. doi: 10.1101/2023.08.28.23294610.

Authors

Yuri L Sosero^{1

2}, Sara Bandres-Ciga³, Bart Ferwerda⁴, Maria T P Tocino^{5

6}, Dìaz R Belloso^{5

6}, Pilar Gómez-Garre^{5

6}, Johann Faouzi^{7

8}, Pille Taba⁹, Lukas Pavelka^{10

11}, Tainà M Marques¹⁰, Clarissa P C Gomes¹², Alexey Kolodkin¹⁰, Patrick May^{10

11}, Lukasz M Milanowski^{13

14}, Zbigniew K Wszolek¹⁴, Ryan J Uitti¹⁴, Peter Heutink¹⁵, Jacobus J van Hilten¹⁶, David K Simon¹⁷, Shirley Eberly¹⁸, Ignacio Alvarez¹⁹, Lynne Krohn^{1

2}, Eric Yu^{1

2}, Kathryn Freeman^{1

2}, Uladzislau Rudakou^{1

2}, Jennifer A Ruskey^{2

20}, Farnaz Asayesh^{2

20}, Manuel Menéndez-Gonzàlez^{21

22

23}, Pau Pastor^{19

24}, Owen A Ross¹⁴, Rejko Krüger^{10

11

12}, Jean-Christophe Corvol⁸, Sulev Koks^{25

26}, Pablo Mir^{5

6

27}, Rob M A De Bie²⁸, Hirotaka Iwaki^{3

29

30}, Ziv Gan-Or^{1

2

20}

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, Canada.
² The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.
³ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes on Health, Bethesda, MD, USA.
⁴ Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
⁵ Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
⁶ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
⁷ Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
⁸ CREST, ENSAI, Campus de Ker-Lann, 51 Rue Blaise Pascal - BP 37203 35172 Bruz Cedex, France.
⁹ Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia.
¹⁰ Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg.
¹¹ Centre Hospitalier de Luxembourg (CHL), Strassen, Luxembourg.
¹² Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
¹³ Department of Neurology Faculty of Health Science, Medical University of Warsaw, Warsaw, Poland.
¹⁴ Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
¹⁵ German Center for Neurodegenerative Diseases (DZNE).
¹⁶ Department of Neurology, Leiden University Medical Center, Leiden.
¹⁷ Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School.
¹⁸ Department of Biostatistics and Computational Biology at the University of Rochester School of Medicine and Dentistry.
¹⁹ Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.
²⁰ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
²¹ Facultad de Medicina y Ciencias de la Salud, Universidad de Oviedo, Calle Julián Clavería s/n, 33006 Oviedo, Spain.
²² Department of Neurology, Hospital Universitario Central de Asturias, Avenida Roma s/n, 33011 Oviedo, Spain.
²³ Instituto de Investigación Sanitaria del Principado de Asturias, Avenida Roma s/n, 33011 Oviedo, Spain.
²⁴ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain.
²⁵ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Australia.
²⁶ Perron Institute for Neurological and Translational Science, Nedlands, Australia.
²⁷ Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
²⁸ Department of Neurology and Clinical Neurophysiology, Amsterdam University Medical Centers, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
²⁹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³⁰ Data Tecnica International, Washington, District of Columbia, USA.

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.

Keywords: GBA1; LRRK2; Parkinson’s disease; dopamine; levodopa-induced dyskinesia.

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Preprint

Abstract

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