Objective: To provide a genome-wide association study (GWAS)- based insight into the genetics of Parkinson’s disease (PD) in Africans and African admixed populations.

Background: Understanding the genetic and mechanistic basis of disease in ancestrally diverse populations is critical to realizing the global application of precision medicine. The African and African admixed populations offer unique opportunities for studying the genetics of monogenic and complex diseases.

Method: We performed a comprehensive genome-wide assessment of PD in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling.

Results: We identified a novel, common, risk factor for PD and age at onset at the GBA1 locus, rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk was via coding mutations, we suggest a novel functional mechanism consistent with a decreasing trend of GBA activity. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant does not cause Gaucher disease.

Conclusion: This study identifies a novel African-specific genetic risk factor and points to GBA1 regulation as a major mechanistic basis for PD in African and African admixed populations. This striking result contrasts to previous work in Northern Europeans, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a crucial point as the field moves toward target-specific PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups. This inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-identifies-novel-etiological-insights-associated-with-parkinsons-disease-in-african-and-african-admixed-populations/