Objective: To compare the clinical manifestations of GBA1 variants p.K198E, p.E326K, and p.N370S in Parkinson’s disease(PD) patients in Colombia.

Background: GBA1 variants have been identified as the most common genetic risk factor for PD[1]. The most prevalent GBA1 variants linked to PD include p.N370S(c.1226A>G) and p.L444P(c.1448T>C),p.E326K(c.1093G>A) all of which have been extensively studied across various populations[2]. A new GBA1 p.K198E(c.594A>G) variant was identified in 5% of Colombian PD patients, causing a 6.5-fold increase in PD risk[3]. This variant has not been reported in other ethnic groups, and it’s clinical implications, particularly in comparison with other common variants in Colombia (p.N370S and p.E326K), remain under investigation[4][5].

Method: Genotyped data from the NeuroBooster Array was available for 718 Colombian individuals and was used to identify 28 individuals carrying p.K198K, p.N370S or p.E326K [6]. 

We performed a comparative statistical analysis to assess significant differences among the three groups. Categorical variables were analyzed using Fisher’s exact test, while continuous variables were compared using the Kruskal-Wallis test. Univariate analysis was conducted to identify potential associations between clinical manifestations and genetic variants.

Results: We identified out of 718 Colombians individuals, 28 individuals carriers of p.N370s, p.E326k and p.K198E.[Table1], [Figure 1],[Figure 2].

A significant difference in dyskinesia prevalence among genotypes(p=0.03) was found,;p.K198E(4 cases), compared to only one p.N370S and no p.E326K carriers ;suggesting a potential genotype influence on dyskinesia susceptibility. Tremor, was also significantly associated with genotype (p=0.02), with p.E326K showing the highest, and p.K198E the lowest prevalence. This relationship is consistent with the literature, which describes tremor as a protective factor against dyskinesias[7]. No significant differences were found in age at onset or most motor and non-motor symptoms.

Conclusion: 3,9% of LARGE PD Colombian PD individuals carry one of 3 GBA1 variants of nearly equal distribution. The p.K198E was associated with increased dyskinesias and less tremor compared with p.E326 k and p.N370S variants. Future studies with larger sample sizes may help clarify these associations and determine the role of GBA1 p.K198E in disease progression and symptom presentation.

Table 1.

Figure 1.

Figure 2.

References: [1] Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651-1661. doi:10.1056/NEJMoa0901281
[2] Rossi M., Schaake S., Usnich T., klein C., et al. Classification and genotype relationships of GBA1 variants: MDSGene systematic review. Movement Disorders 2025. doi: 10.1002/mds.30141
[3] Velez-Pardo C, Lorenzo-Betancor O, Jimenez-Del-Rio M, et al. The distribution and risk effect of GBA variants in a large cohort of PD patients from Colombia and Peru. Parkinsonism Relat Disord. 2019;63:204-208. doi:10.1016/j.parkreldis.2019.01.030
[4] Santos-Lobato, B.L., Schumacher-Schuh, A.F. & Mata, I.F. Lack of full sequencing GBA1 studies for patients with Parkinson’s disease in Latin America. npj Parkinsons Dis. 8, 101 (2022). https://doi.org/10.1038/s41531-022-00358-z
[5] Tipton PW, Soto-Beasley AI, Walton RL, et al. Prevalence of GBA p.K198E mutation in Colombian and Hispanic populations. Parkinsonism Relat Disord. 2020;73:16-18. doi:10.1016/j.parkreldis.2020.03.008
[6] Bandres-Ciga S, Faghri F, Majounie E, et al. NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations. Preprint. medRxiv. 2023;2023.11.06.23298176. Published 2023 Nov 14. doi:10.1101/2023.11.06.23298176
[7] H.M. ChaparroSolano,M. Inca-Martinez, I.F. Mata , et al: Exploring Levodopa-induced dyskinesia in Latin American Parkinsons disease Patients: Insights from the Large-PD Consortium. Parkinsonism Relat Disord. 122(2024). 106085. doi:10.1016/j.parkreldis.2024.106121

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