Carlos Velez-Pardo1, Oswaldo Lorenzo-Betancor2, Marlene Jimenez-Del-Rio3, Sonia Moreno4, Francisco Lopera4, Mario Cornejo-Olivas5, Luis Torres6, Miguel Inca-Martinez7, Pilar Mazzetti8, Carlos Cosentino6, Dora Yearout2, Sarah M Waldherr2, Cyrus P Zabetian2, Ignacio F Mata9. 1. Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Medellín, Antioquia, Colombia. Electronic address: calberto.velez@udea.edu.co. 2. Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. 3. Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Medellín, Antioquia, Colombia. Electronic address: marlene.jimenez@udea.edu.co. 4. Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia (UdeA), Medellín, Antioquia, Colombia. 5. Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru; Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru. 6. Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru; Universidad Nacional Mayor de San Marcos, Lima, Peru. 7. Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. 8. Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru; Universidad Nacional Mayor de San Marcos, Lima, Peru. 9. Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA; Lerner Research Institute, Genomic Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA. Electronic address: matai@ccf.org.
Abstract
BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene are an important risk factor for Parkinson's disease (PD). However, most GBA genetic studies in PD have been performed in patients of European origin and very few data are available in other populations. METHODS: We sequenced the entire GBA coding region in 602 PD patients and 319 controls from Colombia and Peru enrolled as part of the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD). RESULTS: We observed a significantly higher proportion of GBA mutation carriers in patients compared to healthy controls (5.5% vs 1.6%; OR = 4.3, p = 0.004). Interestingly, the frequency of mutations in Colombian patients (9.9%) was more than two-fold greater than in Peruvian patients (4.2%) and other European-derived populations reported in the literature (4-5%). This was primarily due to the presence of a population-specific mutation (p.K198E) found only in the Colombian cohort. We also observed that the age at onset was significantly earlier in GBA carriers when compared to non-carriers (47.1 ± 14.2 y vs. 55.9 ± 14.2 y; p = 0.0004). CONCLUSION: These findings suggest that GBA mutations are strongly associated with PD risk and earlier age at onset in Peru and Colombia. The high frequency of GBA carriers among Colombian PD patients (∼10%) makes this population especially well-suited for novel therapeutic approaches that target GBA-related PD.
BACKGROUND: Mutations in the glucocerebrosidase (GBA) gene are an important risk factor for Parkinson's disease (PD). However, most GBA genetic studies in PD have been performed in patients of European origin and very few data are available in other populations. METHODS: We sequenced the entire GBA coding region in 602 PD patients and 319 controls from Colombia and Peru enrolled as part of the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE-PD). RESULTS: We observed a significantly higher proportion of GBA mutation carriers in patients compared to healthy controls (5.5% vs 1.6%; OR = 4.3, p = 0.004). Interestingly, the frequency of mutations in Colombian patients (9.9%) was more than two-fold greater than in Peruvian patients (4.2%) and other European-derived populations reported in the literature (4-5%). This was primarily due to the presence of a population-specific mutation (p.K198E) found only in the Colombian cohort. We also observed that the age at onset was significantly earlier in GBA carriers when compared to non-carriers (47.1 ± 14.2 y vs. 55.9 ± 14.2 y; p = 0.0004). CONCLUSION: These findings suggest that GBA mutations are strongly associated with PD risk and earlier age at onset in Peru and Colombia. The high frequency of GBA carriers among Colombian PD patients (∼10%) makes this population especially well-suited for novel therapeutic approaches that target GBA-related PD.
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