Objective: This study compares clinical features and disease progression across rs3115534 genotypes (G/G, G/T, T/T) in Nigerians with Parkinson’s disease (PD).

Background: Variants in GBA1 are major global genetic risk factors for PD) The clinical impact of the African‑ancestry–specific GBA1 rs3115534-G variant is unknown.

Method: We conducted a cross-sectional analysis of persons with PD enrolled into GP2 through the Nigeria Parkinson’s Disease Research (NPDR) network. Participants were stratified by GBA1 rs3115534 genotype – G/G, G/T, or T/T. The clinical comparators were sex distribution, age at onset (AAO), proportion of young-onset PD (YOPD) (defined by AAO < 50 years), motor phenotype (Stebbins et al), motor progression rate, and cognitive progression rate. Motor progression was estimated using a linear formula that combined disease duration (months), baseline Hoehn and Yahr (HY) stage, and a pre-assigned HY stage at motor onset of 1. Cognitive trajectory was assessed using the baseline (at study) UPDRS-CF scores (developed by Rosenblum et al.), assuming normal cognition at onset (score 0) and calculating the rate of decline using a similar linear approach.

Results: Data from GP2 Release 11 revealed 2202 PD participants from the NPDR cohort, mean (SD) age – 64.1(10.3) years, 72.4% male, with a median HY (IQR) -of 2 (1)). GBA1 rs3115534 genotypes were distributed as follows: G/G – 295 (13.4%), G/T – 887 (40.3%), T/T – 1020 (46.3%). AAO was significantly lower (p=.000) in G/G (57.6 (10.2) compared to G/T (60.0 (10.5) and T/T (61.1(10.5), with a significantly higher proportion of YOPD in G/G (22.7%) compared to G/T (17.4%) and T/T (12.5%), p=.000). Median disease duration was similar (3.0) across genotypes. Motor phenotype was also similar across all genotypes (predominantly TD, with 57.7% (G/G), 56.0% (G/T), and 54.1% (T/T)). Motor progression and cognitive difficulties did not differ significantly (p = .94 and p = .85, respectively).

Conclusion: The predominant clinical association of the African ancestry-specific GBA1 rs3115534-G is an earlier age at onset and a higher frequency of YOPD.

References: 1. Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. Mov Disord. 2013;28(5):668-670. doi:10.1002/mds.25383
2. Rosenblum S, Meyer S, Richardson A, Hassin-Baer S. Sci Rep. 2022;12(1):22242. Published 2022 Dec 23. doi:10.1038/s41598-022-26280-1
3. GP2 Release 11. 10.5281/zenodo.17753486

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-profile-and-progression-of-parkinsons-disease-in-nigerians-with-the-gba1-african-ancestry-specific-risk-variant/