Characterizing the Genetic Architecture of Parkinson's Disease in Latinos

the 23andMe Research Team, on behalf of the Latin American Research Consortium on the Genetics of Parkinson’s Disease (LARGE-PD)

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalAnnals of Neurology
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a Stanley Fahn Junior Faculty Award (PI: IFM) and an International Research Grants Program award from the Parkinson's Foundation (PI: IFM), by a research grant from the American Parkinson's Disease Association (PI: IFM), and with resources and the use of facilities at the Veterans Affairs Puget Sound Health Care System. This project was partially supported by “The Committee for Development and Research” (Comite para el desarrollo y la investigación‐CODI)‐Universidad de Antioquia grant #2020‐31455 to CV‐P and MJ‐D‐R. TDO was supported by National Human Genome Research Institute of the National Institutes of Health under Award Number R35HG010692. DPL was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number T32HL007698.

Publisher Copyright:
© 2021 American Neurological Association.

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