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 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.

Authors

Institutions

Publication Details

Journal
Brain
Published
2025-10-07
DOI
https://doi.org/10.1093/brain/awaf379
Citations
2
Primary Topic
Nuclear Receptors and Signaling
Type
article
Field-Weighted Citation Impact
1.82

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Fatima Abdulai, David G. Standaert, Raquel Real, Camilla Kilbane et al.
2 citations
Brain
Nuclear Receptors and Signaling
1.82
article

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

Fatima Abdulai, David G. Standaert, Raquel Real, Camilla Kilbane, Whitley W. Aamodt, Clifton L. Dalgard, Chantale Branson, Carlos F. Hernández, Oladunni Abiodun, Chiamaka Okereke, J Solle, Fulya Akçimen, Ahmed O. Idowu, Kristin Levine, Morenikeji Komolafe, Charles Achoru, John Hardy, Rufus Akinyemi, Zih‐Hua Fang, Funmilola Taiwo, Cyril Erameh, Lana M. Chahine, Peter Wild Crea, Kimberly Paquette, Lukman Femi Owolabi, Pilar Álvarez Jerez, Olajumoke Oshinaike, Mahesh Padmanaban, Hampton L. Leonard, Paula Saffie Awad, Paul Suhwan Lee, Shyngle Oyakhire, Christine Klein, Emmanuel Iwuozo, Kolawole Wahab, Alberto J. Espay, Sara Bandrés‐Ciga, Spencer Grant, Ejaz A. Shamim, Lisa Shulman, Mathew J. Koretsky, Frank Imarhiagbe, Elizabeth A. Disbrow, Mary B. Makarious, Roosevelt Anyanwu, Gerald Onwuegbuzie, Erin Furr‐Stimming, Mariam Isayan, Kathryn Step, Vanessa K. Hinson, Laksh Malik, Oluwadamilola O. Ojo, Soraya Bardien, Stewart A. Factor, Christiane Alvarez, Francisca Nwaokorie, Kensuke Daida, Godwin Osaigbovo, Rashidat Olanigan, Ismail O. Ishola, Marissa Dean, Sarah Samuel, Scott A. Norris, Osigwe Agabi, Nosakhare Osemwegie, Olanike Odeniyi, Abdullahi Ibrahim, Yakub Nyandaiti, Cornelis Blauwendraat, Simon Ozomma, Tao Xie, Julia Staisch, Kamalini Ghosh Galvelis, Andrew Ameri, Gauthaman Sukumar, Francis Odiase, Adebimpe Ogunmodede, Deborah J. Hall, Njideka Okubadejo, Huw R. Morris, Henry Houlden, Marzieh Khani, Nabila Dahodwala, Sigvard Åkerman, Paul Nwani, Dan Vitale, Fawzy A. Saad, Ernest Nwazor, FI Ojini, Sani Abubakar, Ashley Rawls, Hirotaka Iwaki, Ewere Marie Ogbimi, Naomi Louie, Nkechi Obianozie, Emily J. Hill, Abiodun Bello, Dena G. Hernandez, Andrew B. Singleton, Erin R. Foster, Daniel Ezuduemoih, Shivika Chandra, Sampath Arepalli, Mike A. Nalls, Wemimo Alaofin, Adedunni Olusanya, Rami Traurig, Sarah Breaux, Alero Nnama, Erica Ikwenu, Raymond Owolabi, Emily Waldo
article en
2 citations

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.

Brain
South African Medical Research Council (ZA), Lagos State University (NG), University of Maryland, Baltimore (US), Ahmadu Bello University (NG), Henry M. Jackson Foundation (US), Rush University Medical Center (US), National Institutes of Health (US), Universidade Federal do Rio Grande do Sul (BR), Cleveland Clinic (US), A. Alikhanyan National Laboratory (AM), Universidad del Desarrollo (CL), Kaiser Permanente (US), University of Ilorin (NG), Johns Hopkins University (US), Uniformed Services University of the Health Sciences (US), Emory University (US), Medical University of South Carolina (US), Queen Mary University of London (GB), University of Pittsburgh (US), University of Ibadan (NG), Benue State University (NG), Delta State University (NG), University of Lagos (NG), Washington University in St. Louis (US), Stellenbosch University (ZA), University Hospitals of Cleveland (US), University of Port Harcourt Teaching Hospital (NG), Ochsner Medical Center (US), Johns Hopkins Medicine (US), University College Hospital, Ibadan (NG), Lagos University Teaching Hospital (NG), The Royal Free Hospital (GB), German Center for Neurodegenerative Diseases (DE), Michael J. Fox Foundation (US), University of Alabama at Birmingham (US), Juntendo University (JP), Cleveland Clinic Lerner College of Medicine (US), University of Calabar (NG), University of Chicago (US), Kaiser Permanente Washington Health Research Institute (US), National Hospital Abuja (NG), Sa'adu Zungur University (NG), Centre for Movement Disorders (CA), National Institute of Neurological Disorders and Stroke (US), University of Benin Teaching Hospital (NG), All Russian Research Institute of Hydrometeorological information World Data Center (RU), Federal Medical Centre (NG), Lagos State University Teaching Hospital (NG), National Institute of Health (AM), University of Abuja Teaching Hospital (NG), Colorado Permanente Medical Group (US), National Institute on Aging (US), Clinica Santa Maria (CL), Nnamdi Azikiwe University Teaching Hospital (NG), Lagos State Health Service Commission (NG), Jos University Teaching Hospital (NG), Lieber Institute for Brain Development (US), National Hospital for Neurology and Neurosurgery (GB), University of Ilorin Teaching Hospital (NG), Irrua Specialist Teaching Hospital (NG), Obafemi Awolowo University Teaching Hospitals Complex (NG), University of Nigeria Teaching Hospital (NG), Parkinson's Foundation (US), University College London (GB), Obafemi Awolowo University (NG), Case Western Reserve University (US), University of Baltimore (US), University of Cincinnati (US), University of Benin (NG), University of Maiduguri (NG), University of Pennsylvania (US), University of Abuja (NG), Louisiana State University Health Sciences Center Shreveport (US), Morehouse College (US), Gombe State University (NG), The University of Texas Health Science Center at Houston (US), Bayero University Kano (NG), University of Lübeck (DE), Rivers State University (NG)
U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Aging
Openalex Percentile: Top 13%
Nuclear Receptors and Signaling
1.82
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.