Douglas P Loesch1,2,3, Andrea R V R Horimoto4, Karl Heilbron5, Elif I Sarihan6, Miguel Inca-Martinez6, Emily Mason6, Mario Cornejo-Olivas7,8, Luis Torres9,10, Pilar Mazzetti7,10, Carlos Cosentino9,10, Elison Sarapura-Castro7, Andrea Rivera-Valdivia7, Angel C Medina11, Elena Dieguez12, Victor Raggio13, Andres Lescano12, Vitor Tumas14, Vanderci Borges15, Henrique B Ferraz15, Carlos R Rieder16, Artur Schumacher-Schuh17,18, Bruno L Santos-Lobato19, Carlos Velez-Pardo20, Marlene Jimenez-Del-Rio20, Francisco Lopera20, Sonia Moreno20, Pedro Chana-Cuevas21, William Fernandez22, Gonzalo Arboleda22, Humberto Arboleda22, Carlos E Arboleda-Bustos22, Dora Yearout23,24, Cyrus P Zabetian23,24, Paul Cannon5, Timothy A Thornton4, Timothy D O'Connor1,2,3, Ignacio F Mata6,23,24. 1. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD. 2. Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD. 3. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. 4. Department of Biostatistics, University of Washington, Seattle, WA. 5. 23andMe, Inc., Sunnyvale, CA. 6. Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH. 7. Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. 8. Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru. 9. Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru. 10. School of Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru. 11. Universidad Nacional del Altiplano, Puno, Peru. 12. Neurology Institute, Universidad de la República, Montevideo, Uruguay. 13. Department of Genetics, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 14. Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, Brazil. 15. Movement Disorders Unit, Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil. 16. Departamento de Neurologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil. 17. Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 18. Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 19. Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, Brazil. 20. Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, Universidad de Antioquia (UdeA), Medellín, Colombia. 21. CETRAM, Facultad de ciencias Medicas, Universidad de Santiago de Chile, Santiago, Chile. 22. Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia. 23. Veterans Affairs Puget Sound Health Care System, Seattle, WA. 24. Department of Neurology, University of Washington, Seattle, WA.
Abstract
OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
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