Objective: The study aimed to investigate genetic risk factors for Parkinson’s disease (PD) in an admixed South African cohort using GWAS and local ancestry (LA)-GWAS approaches, with replication in a Latin American cohort (LARGE-PD), to identify ancestry-specific loci and enhance global understanding of PD susceptibility.

Background: PD is a neurodegenerative disorder with both motor and non-motor symptoms, driven by a strong genetic component. The burden of PD is rising rapidly in aging Sub-Saharan African populations, now ranking as the 11th/12th most prevalent nervous system disorder in the region [1]. Variations in allele frequencies, influenced by factors like natural selection and environmental exposures, can help identify population-specific risk variants in admixed individuals and those relevant across multiple populations.

Method: Using genotyped and imputed data from 691 SA PD cases and 825 controls, we conducted a GWAS using SAIGE software. Moreover, we inferred global and local ancestry for the cohort to better understand the genetic admixture in the SA population and further investigate the GWAS results. Two LA-GWAS approaches were used, one incorporating local ancestry as a covariate (Cochran-Armitage trend test (ATT)) and another by modeling ancestry-specific dosage (Tractor). We assessed replication of our findings using LARGE-PD.

Results: Ancestry inference indicated the SA cohort is admixed with five populations: African, European, Malaysian, Nama, and South Asian. The conventional GWAS identified a significant locus (rs17098735-T; p-value=1.23×10-8) in the AKAP6 gene, associated with PD. Of the 134 lead SNPs, 14 loci replicated in the LARGE-PD cohort. The LA-GWAS ATT model identified one genome-wide significant locus (rs149066239-T; p-value=1.17×10-8) in APBA2, linked to Alzheimer’s disease. Of the suggestive significance variants for ATT, 48 replicated in the LARGE-PD cohort. No genome-wide significant hits were found in the LA-GWAS with Tractor. 

Conclusion: In conclusion, we provide novel genetic insights into PD pathogenicity using a cohort of highly-admixed and genetically diverse South African individuals, highlighting the importance of including genetically diverse and underrepresented populations in PD genetics research.

References: 1. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 23, 344–381 (2024).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-analyses-reveal-susceptibility-variants-linked-to-parkinsons-disease-in-the-south-african-population-using-inferred-global-and-local-ancestry/