Objective: The influence of genetics has been primarily studied in European populations, limiting our understanding of the genetic landscape of PD in the African and African admixed populations. The goal is to bridge this gap which is essential for advancing equitable precision medicine interventions and developing universally effective strategies for the prevention and treatment of PD.

Background: Genetic risk factors and their role on PD in individuals of African and African admixed genetic ancestry remain largely unknown. Around 77% of African genetic studies in PD have been conducted in North Africa (mainly Tunisia) and South Africa. In contrast, there have been limited PD genetic studies in populations originating from Central, Eastern, and the French speaking West coast of Africa. Similarly, the genetics of African admixed individuals have been poorly studied in the context of PD genetics.

Method: We conducted the largest sequencing characterization of potentially disease-causing, protein-altering, and splicing variants in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early-onset and familial cases.

Results: We identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases.

Conclusion: Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/large-scale-genetic-characterization-of-parkinsons-disease-in-the-african-and-african-admixed-populations/