非洲及非洲混血人群帕金森病的大规模遗传特征研究

Elucidating the genetic contributions to Parkinson's disease aetiology across diverse ancestries is a critical priority for 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 ancestries. We explored copy number variants (CNVs) and runs of homozygosity in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 GBA1 variants identified, 10 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, p.Asn409Ser, p.Leu483Pro, p.Thr408Met and p.Glu365Lys, were not identified among the screened Parkinson's disease 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 Parkinson's disease aetiology among West African ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance, with two (p.Glu268Ala and p.Arg1538Cys) displaying higher frequencies in the African ancestry 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 Parkinson's disease in these populations. Short tandem repeat analysis also identified ATXN3 CAG repeat expansions within the pathogenic range (CAGn > 45) in three patients with Parkinson's disease of African ancestry. Novel genetic variation among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalogue of both known and novel coding and splicing variants potentially linked to Parkinson's disease aetiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. 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 Parkinson's disease treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.