Objective: We aimed to assess the distribution of the GBA1 p.K198E variant, linked to Gaucher’s disease (GD) and increased Parkinson’s disease (PD) risk, across Latin America.

Background: GBA1 mutations cause autosomal recessive Gaucher’s disease (GD) and increase PD risk by 3–6-fold [1,2]. The frequency of GBA1 variants varies across populations, occurring in around 5% of PD patients but up to 15–20% in those of Ashkenazi Jewish ancestry [1]. In Latin America, limited studies estimate a 5.4% prevalence [3].

The GBA1 p.K198E variant was identified in 5% of Colombian PD patients causing a 6.5-fold increase in PD risk [4]. A replication study reported lower frequencies with no significant differences between PD patients (2.1%) and controls (1.7%) [5]. However, the variant’s distribution across Latin America remains unexplored, which was the focus of our study.

Method: We screened 4,451 individuals (2,832 affected, 1,619 unaffected) spanning 10 countries through the Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD) [6]. Genotyped data from the Global Diversity+NeuroBooster Array was used to identify candidate individuals carrying the variant [7].

Two different methods were used to validate the presence or absence of the variant: 1) the entire GBA1 gene was amplified in a single fragment, followed by Sanger sequencing with a primer targeting the exon of p.K198E (exon 6) and 2) Oxford Nanopore long-read sequencing of the entire gene.

Results: We identified and validated 8 new GBA1 p.K198E heterozygous carriers, all of whom were PD patients from Colombia (2 Bogota, 2 Cali, 4 Medellin). The variant was detected in 0.18% of those genotyped through LARGE-PD and 1.12% specifically within Colombia. No carriers were found among controls. Fisher’s exact test showed a borderline association between the p.K198E variant and PD (p = 0.057).

Conclusion: Our results support previous findings that the GBA1 p.K198E variant may be unique to Colombian populations. Further investigation is needed to examine a possible founder effect and unique clinical phenotypes associated with GBA1-PD in Colombians carriers.

Table 1

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] Clark LN, Ross BM, Wang Y, et al. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology. 2007;69(12):1270-1277. doi:10.1212/01.wnl.0000276989.17578.02
[3] 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
[4] 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
[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] Zabetian CP, Mata IF; Latin American Research Consortium on the Genetics of PD (LARGE-PD). LARGE-PD: Examining the genetics of Parkinson’s disease in Latin America. Mov Disord. 2017;32(9):1330-1331. doi:10.1002/mds.27081
[7] 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

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MDS Abstracts - https://www.mdsabstracts.org/abstract/screening-for-gba1-p-k198e-pd-risk-variant-in-latin-america/