Large-scale genetic characterization of Parkinson’s disease in the African and African admixed populations
Journal
Brain
ISSN
0006-8950
Date Issued
2025-10-08
Author(s)
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
Type
journal-article
Abstract
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>