Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease

Jodi Maple-Grødem* (Corresponding Author), Ingvild Dalen, Ole-Bjorn Tysnes, Angus Donald MacLeod, Lars Forsgren, Carl Edward Counsell, Guido Alves

*Corresponding author for this work

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Objectives: To establish the significance of GBA-carrier status on motor impairment in a large cohort of patients with incident Parkinson’s disease (PD).
Methods: Three European population-based studies followed 528 patients with PD from diagnosis. 440 with genomic DNA from baseline were assessed for GBA variants. We evaluated motor and functional impairment annually using the Unified PD Rating Scale (UPDRS) motor and Activity of Daily Living (ADL) sections. Differential effects of classes of GBA variants on disease progression were evaluated using mixed random and fixed effects models.
Results: 387 idiopathic patients (age at baseline 70.3±9.5 years; 60.2% male) and 53 GBA-carriers (age at baseline 66.8±10.1 years; 64.2% male) were included. The motor profile of the groups was clinically indistinguishable at diagnosis. GBA-carriers showed faster annual increase in UPDRS scores measuring ADL (1.5 points per year, 95% CI 1.1 to 2.0) and motor symptoms (2.2 points per year, 95% CI 1.3 to 3.1) compared to non-carriers (ADL, 1.0 points per year, 95% CI 0.9 to 1.1, P = 0.003; motor, 1.3 points per year, 95% CI 1.1 to 1.6, P = 0.007). Simulations of clinical trial designs showed that recruiting only GBA-carriers can reduce trial size by up to 65% compared to a trial recruiting all patients with PD.
Conclusion: GBA variants are linked to a more aggressive motor disease course over seven years from diagnosis in patients with PD. A better understanding of PD progression in genetic subpopulations may improve disease management and has direct implications for improving the design of clinical trials.
Original languageEnglish
Pages (from-to)e1036-e1044
Number of pages9
Issue number7
Early online date21 Dec 2020
Publication statusPublished - 16 Feb 2021

Bibliographical note

Study Funding

The Norwegian ParkWest study has been funded by the Research Council of Norway (grant 177966) and the Western Norway Regional Health Authority (grant 911218) and the Norwegian Parkinsons Disease Association. J.M.-G. and G.A. are supported by the Research Council of Norway (grant 287842). PINE was supported by Parkinson’s UK (grants G0502, G0914, and G1302), Scottish Government Chief Scientist Office, BMA Doris Hillier Award, the BUPA Foundation, NHS Grampian Endowments, and RS MacDonald Trust. The NYPUM study has been funded by the Swedish Medical Research Council, the Swedish Parkinson’s Disease Association, the Swedish Parkinson Foundation, and the Västerbotten County Council.


J. Maple-Grødem, I. Dalen, and O.-B. Tysnes report no disclosures relevant to the manuscript. A. Macleod reports fellowship funding from the Scottish Chief Scientist Office (PCL/17/10) and grant funding from the Academy of Medical Sciences and NHS Grampian Endowments. L. Forsgren reports no disclosures relevant to the manuscript. C. Counsell reports NHS Grampian Endowments and RS Macdonald Trust. G. Alves reports Norwegian Research Council grant 287842, principal investigator, 2019–2022 and support from University of Stavanger, Norwegian Parkinson Research Foundation, and Reberg's Legacy. Go to for full disclosures.


The authors thank the patients for participating in the studies; ParkWest thanks all members of the Norwegian ParkWest study group and other personnel involved in the study; NYPUM thanks the study nurse/coordinator Mona Edström and laboratory technician Jörgen Andersson for database management; and PINE thanks the research fellows (Kate Taylor, Robert Caslake, and David McGhee) and study nurses (Clare Harris, Joanna Gordon, Anne Hayman, and Hazel Forbes) who assessed participants, the secretaries (Susan Kilpatrick and Pam Rebecca), the data management team (Katie Wilde and David Ritchie), and the clinicians who referred patients to the PINE study.


  • Activities of Daily Living
  • Aged
  • Aged, 80 and over
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Glucosylceramidase/genetics
  • Humans
  • Male
  • Mental Status and Dementia Tests
  • Middle Aged
  • Mutation
  • Parkinson Disease/genetics


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