| Title: |
Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations |
| Authors: |
Akçimen, Fulya; Paquette, Kimberly; Wild Crea, Peter; Step, Kathryn; Waldo, Emily; Koretsky, Mathew J; Saffie-Awad, Paula; Achoru, Charles; Taiwo, Funmilola; Ozomma, Simon; Onwuegbuzie, Gerald; Khani, Marzieh; Grant, Spencer; Owolabi, Lukman; Okereke, Chiamaka; Oshinaike, Olajumoke; Iwuozo, Emmanuel; Can Akerman, Suleyman; Lee, Paul Suhwan; Oyakhire, Shyngle; Osemwegie, Nosakhare; Daida, Kensuke; Abubakar, Sani; Olusanya, Adedunni; Isayan, Mariam; Alvarez, Christiane; Traurig, Rami; Ogunmodede, Adebimpe; Samuel, Sarah; Makarious, Mary B; Sa'ad, Fadimatu; Olanigan, Rashidat; Levine, Kristin; Ogbimi, Ewere Marie; Vitale, Dan; Odiase, Francis; Ojini, Francis; Odeniyi, Olanike; Fang, Zih-Hua; Obianozie, Nkechi; Hall, Deborah A; Nwazor, Ernest; Xie, Tao; Nwaokorie, Francesca; Padmanaban, Mahesh; Nwani, Paul; Shamim, Ejaz A; Nnama, Alero; Standaert, David; Komolafe, Morenikeji; Dean, Marissa; Osaigbovo, Godwin; Disbrow, Elizabeth; Ishola, Ismaila; Rawls, Ashley; Imarhiagbe, Frank; Chandra, Shivika; Erameh, Cyril; Hinson, Vanessa; Louie, Naomi; Idowu, Ahmed; Solle, J; Norris, Scott A; Ibrahim, Abdullahi; Kilbane, Camilla; Sukumar, Gauthaman; Shulman, Lisa M; Ezuduemoih, Daniel; Staisch, Julia; Breaux, Sarah; Dalgard, Clifton; Foster, Erin R; Bello, Abiodun; Ameri, Andrew; Real, Raquel; Ikwenu, Erica; Morris, Huw R; Anyanwu, Roosevelt; Furr Stimming, Erin; Billingsley, Kimberley; Alaofin, Wemimo; Alvarez Jerez, Pilar; Agabi, Osigwe; Hernandez, Dena G; Akinyemi, Rufus; Arepalli, Sampath; Malik, Laksh; Owolabi, Raymond; Nyandaiti, Yakub; Leonard, Hampton L; Wahab, Kolawole; Abiodun, Oladunni; Hernandez, Carlos F; Abdulai, Fatima; Iwaki, Hirotaka; Bardien, Soraya; Klein, Christine; Hardy, John; Houlden, Henry; Galvelis, Kamalini Ghosh; Nalls, Mike A; Dahodwala, Nabila; Aamodt, Whitley; Hill, Emily; Espay, Alberto; Factor, Stewart; Branson, Chantale; Blauwendraat, Cornelis; Singleton, Andrew B; Ojo, Oluwadamilola; Chahine, Lana M; Okubadejo, Njideka; Bandres-Ciga, Sara |
| Source: |
Brain , Article awaf379. (2025) (In press). |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2025 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
African ancestry; Black and African American population; Parkinson’s disease; disease-causing mutations; genetics |
| Description: |
Elucidating the genetic contributions to Parkinson's disease (PD) etiology 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 (ROHs) in prioritized early onset and 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 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 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. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which-p.Glu268Ala and p.Arg1538Cys-had a higher prevalence 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 PD in these populations. Short tandem repeat analysis also identified ATXN3 repeat expansions within the pathogenic range (CAGn > 45) in three PD patients of ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10215404/1/awaf379.pdf; https://discovery.ucl.ac.uk/id/eprint/10215404/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10215404/1/awaf379.pdf; https://discovery.ucl.ac.uk/id/eprint/10215404/ |
| Rights: |
open |
| Accession Number: |
edsbas.19CFA3E7 |
| Database: |
BASE |