Characterizing the Genetic Architecture of Parkinson's Disease in Latinos

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

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas

“…This includes whole-genome sequencing (WGS) data from admixed individuals of the 1000 Genomes Project ( 1000 Genomes Project Consortium, Auton et al, 2015 ) [African Americans from Southwest United States (ASW); African Caribbeans from Barbados (ACB); individuals of Mexican ancestry from Los Angeles, United States (MXL); Puerto Ricans from Puerto Rico (PUR); and Colombians from Medellin (CLM)], as well as WGS data from individuals of the TOPMED Project ( Taliun et al, 2021 ) (individuals from the Dominican Republic and Cuba from HCHS/SOL cohort, and individuals from Costa Rica from CRA cohort) and the Peruvian Genome Project ( Harris et al, 2018 ). We also included genotype array data from the LARGE-PD Project ( Loesch et al, 2020 ) (individuals from Brazil, Colombia, Chile, and Uruguay), two Brazilian EPIGEN population-based cohorts ( Kehdy et al, 2015 ) (individuals from Salvador and Bambui), and from admixed and Native American individuals of the Peruvian Genome Project ( Harris et al, 2018 ; Borda et al, 2020 ). All these datasets were generated from different sources ( Supplementary Table 1 ) but include the –13910C > T SNP (rs4988235).…”

Mapping the Diverse and Inclusive Future of Parkinson’s Disease Genetics and Its Widespread Impact

“…The new era of PD genetics holds promise. Genetic studies conducted in underrepresented populations have started to emerge [55][56][57] as well as consortium setups [58] (GP2, https://www.gp2.org/, accessed on 20 September 2021) with programs strongly focused on increasing diversity in PD research so that the applications of genetic discoveries can be extrapolated to the entire population. As a result, an important analytical approach in our field will be the implementation of trans-ethnic GWAS meta-analysis, such as GWAMA [57] and MANTRA [59], that will allow us to combine genetic information from different ancestries to further delineate the etiology of this complex disease.…”

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson’s disease cohort

“…In addition, the lead SNP is a variant in SNCA, as would be expected given prior PD GWAS results. 3,6 To validate the GWAS-significant PRS and the PRS-full, we tested both models in a cohort of 448 Latinos provided by the IPDGC. The GWAS-significant model had an AUC of 0.665 with a balanced accuracy of 59.6%, a sensitivity of 61.3% and a specificity of 60.0% (see Table 1).…”

“…4 Diversity in PD research is increasing: Foo et al 2020 have conducted the largest study of PD patients with East Asian ancestry 5 and our group has conducted the largest study of South American PD patients. 6 Outside of risk variant and disease-gene discovery, a primary use of GWAS is to generate summary statistics for the purpose of risk prediction using polygenic risk scores (PRS). A PRS is the linear summation of disease risk variants weighted by their regression effect size and has been shown to improve disease risk prediction.…”

“…5 Here, we construct a PRS using summary statistics from Nalls et al 2019 3 and tested it in our Latino case-control cohort from the Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD). 6,12 In addition, we seek to characterize the distribution of PD risk alleles and the PD PRS across diverse global populations via the 1000 Genome Project 13 and the Peruvian Genome Project. 14 We also explore the haplotype structure of rs356182 near SNCA, a major component of the PD PRS and thought to be a key gene in PD etiology 15 , across ancestrally diverse populations.…”