Abstract
We aimed to replicate a recent study that found a high frequency of the GBA p.K198E mutant in Colombian patients with PD. We identified the p.K198E substitution at a lower frequency in our cohort of Colombians with PD (2.1%), and this was not significantly different than controls (1.7%, P = 0.86) emphasizing the need for larger genetic studies in Latin America.
Keywords: Parkinson’s disease, Genetics, GBA, Gaucher’s disease
Recessive mutation of the glucocerebrosidase (GBA) gene causes Gaucher’s disease (GD) and heterozygous carrier status is one of the strongest genetic risk factors for Parkinson’s disease (PD) [1]. Patients with PD carrying a GBA mutation most commonly have the p.N370S or p.L444P mutations based on ethnicity, and population studies have consisted mostly of patients from the United States, Europe, and Asia, with relatively little information on patients from Latin America [1]. A recent study found a significant association of GBA mutations in Colombians (9.9% of patients compared to 1.8% in controls) with PD [2]. The higher frequency in Colombians was due to the fact that more than half of GBA mutation carriers in that population possessed a p.K198E substitution; while the remaining carriers were equally divided between p.N370S and p.L444P mutations. In order to address the paucity of information regarding PD genetics in Latin America, we aimed to replicate the high frequency of the p.K198E substitution in an independent cohort of Colombians with both PD and controls as well as a cohort of American Hispanics.
We screened genomic DNA for the GBA chr1:155207977 A > G (rs773409311; p.K198E) variant in 209 unrelated PD patients, including 142 Colombians and 67 Hispanic Americans, and 58 healthy controls (Table 1). All participants were accrued on an opportunistic basis and evaluated by a movement disorder specialist. All components of this study were approved by the institutional review board at each site. A signed consent form was obtained from all participants prior to their enrollment in the study. Detailed methods are provided in the supplemental materials. The average age at enrollment (AAE) was similar across all groups, while age of onset (AAO) was 6.2 years later in Hispanic PD cases compared to PD cases from Colombia. Among Colombian PD cases, 44.7% were EOPD defined as AAO ≤50 years old. Only 20.9% of the American Hispanic PD cases were EOPD. We identified three carriers (2.1%) of the GBA p.K198E substitution in the Colombian PD cohort, and one carrier (1.7%) in the Colombian control cohort; p.K198E was not significantly associated with risk of PD in Colombians in unadjusted logistic regression analysis (Odds ratio = 1.23, 95% confidence interval: 0.13–12.07, P = 0.86) or when adjusting for age and sex (Odds ratio = 1.63, 95% confidence interval: 0.16–16.39, P = 0.68). There were no GBA p.K198E carriers in the American Hispanic group (P = 0.46 vs. controls).
Table 1.
Series demographics.
| Colombia | Hispanic | Velez-Pardo et al. | |||
|---|---|---|---|---|---|
| PD | CTRL | PD | PD | CTL | |
| N | 142 | 58 | 67 | 131 | 164 |
| N males (%) | 75 (53%) | 21 (36%) | 41 (61%) | 63 (49.2) | 82 (50) |
| AAE, y | 62.7 ± 11.5 | 58.9 ± 13.3 | 63.5 ± 12.7 | 64.6 ± 13.4 | 53.8 ± 14.1 |
| (Range) | (29–87) | (34–101) | (36–89) | (28–92) | (20–82) |
| AAO, y | 53.2 ± 13.0 | N/A | 59.4 ± 14.3 | 49.3 ± 16.4 | N/A |
| (Range) | (20–85) | N/A | (32–83) | (9–82) | N/A |
| EOPD (%) | 44.7 | N/A | 20.9 | 46.9 | N/A |
| p.K198E Carriers (%) | 3 (2.1) | 1 (1.7) | 0 | 7 (6.0) | 2 (1.3) |
AAE = age at enrollment; AAO = age at onset; EOPD = Early-Onset PD (≤ 50 years old); N = sample size N/A = not applicable; PD = Parkinson’s disease; y = years.
We found a lower prevalence of p.K198E among PD patients compared to Velez-Pardo and colleagues [2]. Our sample size of Colombian patients with PD is slightly larger with a similar average AAO (53.2 vs. 49.3) and comparable percentage of patients with EOPD (44.7% vs. 46.9%) [2]. Several GBA mutations have been associated with earlier onset of PD in non-Colombian Latin American populations; however, p.K198E was not among the genetic mutations identified [3]. Nevertheless, if p.K198E had a similar effect on AAO, then this may be a factor contributing to the discrepancy between our respective p.K198E frequencies as well as the Hispanic Americans, which were roughly 10 years older than the Velez-Pardo cohort.
The most plausible explanation for a difference in p.K198E prevalence between Velez-Pardo’s and our PD cases is sample heterogeneity. While Colombia has a diverse population, all carriers in our study were of Amerindian descent with ancestry from Cundinamarca (n = 2), Santander (n = 1), and Caldas/Santander (n = 1). This suggests that p.K198E may have originated in the Colombian Amerindian population. This is further supported by the absence of p.K198E in our American Hispanic cohort as well as other studies, which failed to find p.K198E in non-Colombian individuals [2–4]. Mutation carriers within the study by Velez-Pardo and colleagues were from Antioquia, where a founder effect has been previously described with parkin mutations [5]. Our mutation carriers’ ancestry is traced to other Colombian departments adjacent to Antioquia where the potential for a founder effect is less clear.
Our study is a close comparator to the recent study by Velez-Pardo and colleagues. Differences in GBA p.K198E frequency highlights several variables that can affect genetic study results. Thus, larger studies are warranted with the intent of sampling large geographic regions with detailed documentation of each participant’s ancestry. While Latin America, as a whole, is poorly represented in PD genetics literature, more specific populations of Africans and Amerindians of Latin America should be a major focus.
Supplementary Material
Acknowledgements
Mayo Clinic is an American Parkinson Disease Association (APDA) Information and Referral Center and APDA Center for Advanced Research. We would like to thank Ms. Anne Martin and Ms. Audrey Strongosky who were involved in logistics of sample collections, Mayo IRB approvals, clinical data storage and sample collection handling and deidentification procedures. We also thank Ms. Beatriz A. Heilbron from the Mayo Clinic International Business Office in Bogota, Colombia.
Declaration of competing interest
Dr. Tipton: Reports no disclosures.
Ms. Soto-Beasley: Reports no disclosures.
Mr. Walton: Reports no disclosures.
Dr. Silvia Soler: Reports no disclosures.
Dr. Romero-Osorio: Reports no disclosures.
Dr. Díaz: Reports no disclosures.
Dr. Moreno-López:
Dr. Ross: received support from R01 NS078086, P50 NS072187, U54 NS100693, U54 NS110435, the US Department of Defense (W81XWH-17-1-0249), the Mayo Clinic LBD Functional Genomics Program, The Little Family Foundation, and the Michael J. Fox Foundation. O.A.R. is an editorial board member of American Journal of Neurodegenerative Disease, Frontiers of Neurology: Neurogenetics and Molecular Neurodegeneration.
Dr. Wszolek: ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or Co-PI on Abbvie, Inc. (M15-562, M15-563, and laboratory based grant), Biogen, Inc. (228PD201), and BioHaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301) grants. He serves as PI of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as Co-PI of the Mayo Clinic APDA Center for Advanced Research.
Dr. Cerquera Cleves: Reports no disclosures.
Glossary
- AAO
Age at onset
- AAE
Age at enrollment
- EOPD
Early onset Parkinson’s disease
- GD
Gaucher’s disease
- GBA
glucocerebrosidase
- LOPD
Late onset Parkinson’s disease
- PD
Parkinson’s disease
Footnotes
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.parkreldis.2020.03.008.
Contributor Information
Philip W. Tipton, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Mangurian Building, Jacksonville, FL, 32224, USA
Alexandra I. Soto-Beasley, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
Ronald L. Walton, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
Silvia Soler-Rangel, Movement Disorders Clinic, Hospital Universitario San Ignacio, Bogota, Colombia; School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia.
Óscar Romero-Osorio, Movement Disorders Clinic, Hospital Universitario San Ignacio, Bogota, Colombia; School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia.
Cindy Díaz, Movement Disorders Clinic, Hospital Universitario San Ignacio, Bogota, Colombia; School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia.
Claudia Lucía Moreno-López, Movement Disorders Clinic, Hospital Universitario San Ignacio, Bogota, Colombia; Fundación Cardioinfantil, Bogotá, Colombia.
Owen A. Ross, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA Department of Clinical Genomics, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.
Zbigniew K. Wszolek, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Mangurian Building, Jacksonville, FL, 32224, USA.
Catalina Cerquera-Cleves, Movement Disorders Clinic, Hospital Universitario San Ignacio, Bogota, Colombia; School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia; Clínica Universitaria Colombia, Bogotá, Colombia.
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