Large-scale genetic characterization of Parkinson′s disease in the African and African admixed populations

Elucidating the genetic contributions to Parkinson′s disease (PD) etiology across diverse ancestries is a critical priority in the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease—causing protein—altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed populations. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset or familial cases. Our study 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 with uncertain clinical significance. The most common known disease—causing GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the 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 African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented among cases, two of which — p.Glu268Ala and p.Arg1538Cys — had a higher prevalence in the general African ancestry in population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early—onset cases, providing further insights into the genetic underpinnings in early—onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to better understand their pathogenic potential. 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. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.