| Title: | Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations |
| Journal: | Brain |
| Published: | 8 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41058593/ |
| DOI: | https://doi.org/10.1093/brain/awaf379 |
| URL: | https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awaf379/64544330/awaf379.pdf |
Publication 19255
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Abstract
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 African ancestry. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel 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 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 PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.</p>
113 Authors
- Fulya Akçimen
- Kimberly Paquette
- Peter Wild Crea
- Kathryn Step
- Emily Waldo
- Mathew J Koretsky
- Paula Saffie-Awad
- Charles Achoru
- Funmilola Taiwo
- Simon Ozomma
- Gerald Onwuegbuzie
- Marzieh Khani
- Spencer Grant
- Lukman Owolabi
- Chiamaka Okereke
- Olajumoke Oshinaike
- Emmanuel Iwuozo
- Suleyman Can Akerman
- Paul Suhwan Lee
- Shyngle Oyakhire
- Nosakhare Osemwegie
- Kensuke Daida
- Sani Abubakar
- Adedunni Olusanya
- Mariam Isayan
- Christiane Alvarez
- Rami Traurig
- Adebimpe Ogunmodede
- Sarah Samuel
- Mary B Makarious
- Fadimatu Sa'ad
- Rashidat Olanigan
- Kristin Levine
- Ewere Marie Ogbimi
- Dan Vitale
- Francis Odiase
- Francis Ojini
- Olanike Odeniyi
- Zih-Hua Fang
- Nkechi Obianozie
- Deborah A Hall
- Ernest Nwazor
- Tao Xie
- Francesca Nwaokorie
- Mahesh Padmanaban
- Paul Nwani
- Ejaz A Shamim
- Alero Nnama
- David Standaert
- Morenikeji Komolafe
- Marissa Dean
- Godwin Osaigbovo
- Elizabeth Disbrow
- Ismaila Ishola
- Ashley Rawls
- Frank Imarhiagbe
- Shivika Chandra
- Cyril Erameh
- Vanessa Hinson
- Naomi Louie
- Ahmed Idowu
- J Solle
- Scott A Norris
- Abdullahi Ibrahim
- Camilla Kilbane
- Gauthaman Sukumar
- Lisa M Shulman
- Daniel Ezuduemoih
- Julia Staisch
- Sarah Breaux
- Clifton Dalgard
- Erin R Foster
- Abiodun Bello
- Andrew Ameri
- Raquel Real
- Erica Ikwenu
- Huw R Morris
- Roosevelt Anyanwu
- Erin Furr Stimming
- Kimberley Billingsley
- Wemimo Alaofin
- Pilar Alvarez Jerez
- Osigwe Agabi
- Dena G Hernandez
- Rufus Akinyemi
- Sampath Arepalli
- Laksh Malik
- Raymond Owolabi
- Yakub Nyandaiti
- Hampton L Leonard
- Kolawole Wahab
- Oladunni Abiodun
- Carlos F Hernandez
- Fatima Abdulai
- Hirotaka Iwaki
- Soraya Bardien
- Christine Klein
- John Hardy
- Henry Houlden
- Kamalini Ghosh Galvelis
- Mike A Nalls
- Nabila Dahodwala
- Whitley Aamodt
- Emily Hill
- Alberto Espay
- Stewart Factor
- Chantale Branson
- Cornelis Blauwendraat
- Andrew B Singleton
- Oluwadamilola Ojo
- Lana M Chahine
- Njideka Okubadejo
- Sara Bandres-Ciga
1 Application
| Application ID | Title |
|---|---|
| 33601 | Dissecting the genetic architecture of neurodegenerative diseases |
Enabling scientific discoveries that improve human health