Genome-wide association analyses reveal susceptibility variants linked to Parkinson's disease in the South African population using inferred global and local ancestry.

Genome-wide association studies (GWAS) have been successful in identifying over 100 loci associated with Parkinson's disease (PD) susceptibility. However, the majority of these studies have focused on European cohorts with few including diverse ancestries. Using genotyped and imputed data from 691 South African PD cases and 826 controls, we conducted a conventional GWAS, two local ancestry GWAS (LA-GWAS) approaches (one using local ancestry as a covariate and the other separating the dosage per ancestry), and an association analysis to identify regions of homozygosity associated with PD status. Furthermore, we replicated these findings using another admixed population, a Latin American cohort (LARGE-PD). The ancestry inference suggested that the South African cohort is admixed from five populations, including African (AFR), European (EUR), Malaysian (MAL), Nama (NAMA), and South Asian (SAS), though with varying accuracy levels. The conventional GWAS successfully identified one locus (rs17098735-T) with genome-wide significance (p-value: 1.23×10; beta= 2.286; SE= 0.401). Within the local ancestry window of the top GWAS hit, among individuals carrying the variant, 86.7% had AFR ancestry, 11% NAMA ancestry, and 2.2% MAL ancestry, with no EUR or SAS ancestry observed, highlighting a potential ancestry-specific genetic risk factor. Three lead loci were replicated in the LARGE-PD cohort. LA-GWAS using the Cochran-Armitage trend test identified 35 lead SNPs above suggestive significance after multiple test correction. Tractor-based approaches identified three lead loci when analyzing all five ancestry components jointly, as well as three additional lead loci in the AFR-only component, highlighting ancestry-specific loci that may contribute to genetic risk in diverse populations. For the LA-GWAS, one independent locus was replicated in LARGE-PD. Our findings suggest ancestry specificity in PD risk and underscores the importance of including diverse populations in genetics research. The study contributes towards a global understanding of the genetic etiology underlying PD.