Objective: By performing the first genome-wide association study (GWAS) of Parkinson’s disease (PD) in Latinos, we seek to interrogate the genetic architecture of PD in a South American cohort. [1]

Background: PD is the fastest-growing neurodegenerative disease with an increasing burden on healthcare systems worldwide . Despite its prevalence in all ethnic groups, large-scale studies of genetic variation conferring PD risk have been limited to subjects of European and East Asian descent. We conduct the first GWAS of PD in South America, characterize the linkage disequilibrium (LD) structure of risk variants in SNCA, and perform a replication of GWAS-significant variants identified by Nalls et al. [2]

Method: We genotyped 1497 subjects (807 PD cases) from the Latin American Research Consortium on the Genetics of PD (LARGE-PD) with the MEGA chip from Illumina, followed by standard quality control and imputation using the Trans-omics for Precision Medicine (TOPMed) imputation server. We tested variants for association with PD using a generalized linear mixed model as implemented in the GENESIS R package, adjusting for age, sex, the first 5 PCs, and relatedness. For the replication of variants found by Nalls et al., we employed the unrelated subset of LARGE-PD and logistic regression in PLINK.

Results: We found two loci with genome-wide significance (p-value < 5×10-08), one in chromosome 3 near NRROS and one in chromosome 4 in SNCA. The chromosome 3 result is driven by the Peruvian subset of our cohort and is likely of Amerindian origin; chromosome 4 locus is well-characterized in the PD literature. Significant LD is observed between GWAS-significant SNCA variants and is higher overall in the Peruvian subset. Out of the 84 variants we tested from Nalls et al., 69 were concordant in their direction of effect and 11 were nominally significant. One variant in SNCA, rs356182, replicated and is genome-wide significant in our primary GWAS.

Conclusion: We affirmed the importance of SNCA, and in particular rs356182, to PD etiology in South America and identified a possible population-specific risk variant near NRROS, a gene involved in microglial function. The NRROS result needs to be replicated in an independent cohort with significant Native American ancestry. The overall concordance between the results of Nalls et al. and our replication indicate similarities in genetic architecture.

References: [1] Submitted on behalf of the Latin American Research Consortium on the Genetics of PD (LARGE-PD) [2] Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18(12):1091-1102. doi:10.1016/S1474-4422(19)30320-5

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterizing-the-genetic-architecture-of-parkinsons-disease-in-latinos/