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[Preprint]. 2025 Jan 20:2025.01.14.25320205.

doi: 10.1101/2025.01.14.25320205.

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

Fulya Akçimen¹, Kimberly Paquette², Peter Wild Crea^{1

2}, Paula Saffie-Awad^{3

4}, Charles Achoru⁵, Funmilola Taiwo⁶, Simon Ozomma⁷, Gerald Onwuegbuzie⁸, Marzieh Khani², Spencer Grant^{1

2}, Lukman Owolabi⁹, Chiamaka Okereke¹⁰, Olajumoke Oshinaike¹¹, Emmanuel Iwuozo¹², Paul Suhwan Lee¹, Shyngle Oyakhire¹³, Nosakhare Osemwegie¹⁴, Kensuke Daida^{1

2

15}, Sani Abubakar¹⁶, Adedunni Olusanya^{17

18}, Mariam Isayan¹⁹, Rami Traurig², Adebimpe Ogunmodede²⁰, Sarah Samuel²¹, Mary B Makarious^{2

22}, Fadimatu Sa'ad²³, Rashidat Olanigan²⁴, Kristin Levine^{2

22}, Ewere Marie Ogbimi²⁵, Dan Vitale^{2

22}, Francis Odiase²⁶, Mathew J Koretsky^{2

22}, Francis Ojini^{17

27}, Olanike Odeniyi²⁸, Zih-Hua Fang²⁹, Nkechi Obianozie³⁰, Deborah A Hall³¹, Ernest Nwazor³², Tao Xie³³, Francisca Nwaokorie¹⁷, Mahesh Padmanaban³³, Paul Nwani³⁴, Ejaz A Shamim^{35

36

37}, Alero Nnama¹⁴, David Standaert³⁸, Morenikeji Komolafe³⁹, Marissa Dean³⁸, Godwin Osaigbovo⁵, Elizabeth Disbrow⁴⁰, Ismaila Ishola¹⁷, Ashley Rawls⁴¹, Frank Imarhiagbe²⁶, Shivika Chandra⁴², Cyril Erameh⁴³, Vanessa Hinson⁴⁴, Naomi Louie⁴⁵, Ahmed Idowu⁴⁶, J Solle⁴⁵, Scott A Norris⁴⁷, Abdullahi Ibrahim⁴⁸, Camilla Kilbane⁴⁹, Gauthaman Sukumar^{50

51}, Lisa M Shulman⁵², Daniel Ezuduemoih²⁷, Julia Staisch⁵³, Sarah Breaux⁵³, Clifton Dalgard^{54

55}, Erin R Foster⁴⁷, Abiodun Bello⁵⁶, Andrew Ameri⁴⁴, Raquel Real^{57

58}, Erica Ikwenu²⁷, Huw R Morris^{57

59

60}, Roosevelt Anyanwu¹⁷, Erin Furr Stimming⁴², Kimberley Billingsley², Wemimo Alaofin⁶¹, Pilar Alvarez Jerez^{1

57}, Osigwe Agabi^{17

27}, Dena G Hernandez¹, Rufus Akinyemi⁶², Sampath Arepalli¹, Laksh Malik², Raymond Owolabi²⁰, Yakub Nyandaiti²¹, Hampton L Leonard^{2

22}, Kolawole Wahab⁶¹, Kathryn Step⁶³, Oladunni Abiodun⁶⁴, Carlos F Hernandez⁶⁵, Fatima Abdulai³⁰, Hirotaka Iwaki^{2

22}, Soraya Bardien⁶³, Christine Klein⁶⁶, John Hardy⁶⁷, Henry Houlden⁶⁸, Kamalini Ghosh Galvelis⁶⁹, Mike A Nalls^{2

22}, Nabila Dahodwala⁷⁰, Whitley Aamodt⁷⁰, Emily Hill⁷¹, Alberto Espay⁷¹, Stewart Factor⁷², Chantale Branson⁷³, Cornelis Blauwendraat^{1

2}, Andrew B Singleton^{1

2}, Oluwadamilola Ojo^{17

27}, Lana M Chahine⁷⁴; Black and African American Connections to Parkinson’s Disease Study (BLAAC PD); Nigeria Parkinson’s Disease Research Network (NPDRN); Racial Disparities in Parkinson Disease (RaD-PD); Global Parkinson’s Genetics Program (GP2); Njideka Okubadejo^{17

27}, Sara Bandres-Ciga²

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
³ Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁴ Clínica Santa María, Santiago, Chile.
⁵ Jos University Teaching Hospital, Jos, Plateau State, Nigeria.
⁶ University College Hospital, Ibadan, Oyo State, Nigeria.
⁷ University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.
⁸ University of Abuja, Abuja, Federal Capital Territory, Nigeria.
⁹ Bayero University, Kano, Kano State, Nigeria.
¹⁰ University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, Nigeria.
¹¹ Lagos State University College Of Medicine, Ikeja, Lagos State, Nigeria.
¹² Benue State University, Makurdi, Benue State, Nigeria.
¹³ National Hospital Abuja, Federal Capital Territory, Nigeria.
¹⁴ University of Port Harcourt Teaching Hospital, Rivers State, Nigeria.
¹⁵ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan.
¹⁶ Ahmadu Bello University, Zaria, Kaduna State, Nigeria.
¹⁷ College of Medicine, University of Lagos, Idi-araba, Lagos State, Nigeria.
¹⁸ R-Jolad Hospital, Gbagada, Lagos, Nigeria.
¹⁹ Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.
²⁰ Federal Medical Center, Owo, Ondo State, Nigeria.
²¹ University of Maiduguri Teaching Hospital, Maiduguri, Borno State.
²² DataTecnica LLC, Washington, DC, USA.
²³ Federal Teaching Hospital, Gombe, Gombe State, Nigeria.
²⁴ Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria.
²⁵ Delta State University, Abraka, Delta State, Nigeria.
²⁶ University of Benin, Benin City, Edo State, Nigeria.
²⁷ Lagos University Teaching Hospital, Idi-araba, Lagos State, Nigeria.
²⁸ General Hospital, Lagos Island, Lagos State, Nigeria.
²⁹ German Center for Neurodegenerative Diseases, DZNE, Tübingen, Germany.
³⁰ University of Abuja Teaching Hospital, Gwagwalada, Federal Capital Territory, Nigeria.
³¹ Department of Neurological Sciences, Rush University Medical Center, Chicago, USA.
³² Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria.
³³ University of Chicago Medicine, Department of Neurology, Chicago, USA.
³⁴ Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria.
³⁵ National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³⁶ Mid-Atlantic Permanente Medical Group, Department of Neurology, Largo, MD, USA.
³⁷ Kaiser Permanente, MidAtlantic Permanente Research Institute, Washington, DC, USA.
³⁸ University of Alabama at Birmingham, Department of Neurology, Birmingham, USA.
³⁹ Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.
⁴⁰ Department of Neurology, LSU Health Shreveport, LSU Health Shreveport Center for Brain Health, Shreveport, USA.
⁴¹ University of Florida Norman Fixel Institute for Neurological Diseases, Neurology Movement Disorders, Gainesville, USA.
⁴² The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴³ Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria.
⁴⁴ Medical University of South Carolina, Charleston, SC, USA.
⁴⁵ Michael J. Fox Foundation for Parkinson's Research, Department of Clinical Research, New York, USA.
⁴⁶ Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria.
⁴⁷ Washington University in St. Louis, St. Louis, MO, USA.
⁴⁸ Federal University of Health Sciences Teaching Hospital, Azare, Bauchi State, Nigeria.
⁴⁹ University Hospital in Cleveland Medical Center/Case Western Reserve University (UH).
⁵⁰ Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services.
⁵¹ University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
⁵² University of Maryland, Baltimore, MD, USA.
⁵³ Ochsner Clinic Foundation, New Orleans, LA, USA.
⁵⁴ Henry M. Jackson Foundation for the Advancement of Military Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵⁵ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
⁵⁶ University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria.
⁵⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
⁵⁸ UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
⁵⁹ National Hospital for Neurology and Neurosurgery, London, UK.
⁶⁰ Department of Neurology, Royal Free Hospital, London, UK.
⁶¹ University of Ilorin, Ilorin, Kwara State, Nigeria.
⁶² Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
⁶³ Department of Biomedical Sciences, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁶⁴ General Hospital, Isolo, Lagos State, Nigeria.
⁶⁵ Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago 7610658, Chile.
⁶⁶ Institute of Neurogenetics and Department of Neurology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.
⁶⁷ Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.
⁶⁸ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁶⁹ Parkinson's Foundation, NewYork, NY 10018, USA.
⁷⁰ University of Pennsylvania, Philadelphia, PA.
⁷¹ University of Cincinnati, Cincinnati, Ohio.
⁷² Emory University, Atlanta, GA.
⁷³ Morehouse College, Atlanta, GA.
⁷⁴ University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA.

PMID: 39867380
PMCID: PMC11759243
DOI: 10.1101/2025.01.14.25320205

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

Fulya Akçimen et al. medRxiv. 2025.

[Preprint]. 2025 Jan 20:2025.01.14.25320205.

doi: 10.1101/2025.01.14.25320205.

Authors

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
³ Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁴ Clínica Santa María, Santiago, Chile.
⁵ Jos University Teaching Hospital, Jos, Plateau State, Nigeria.
⁶ University College Hospital, Ibadan, Oyo State, Nigeria.
⁷ University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.
⁸ University of Abuja, Abuja, Federal Capital Territory, Nigeria.
⁹ Bayero University, Kano, Kano State, Nigeria.
¹⁰ University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, Nigeria.
¹¹ Lagos State University College Of Medicine, Ikeja, Lagos State, Nigeria.
¹² Benue State University, Makurdi, Benue State, Nigeria.
¹³ National Hospital Abuja, Federal Capital Territory, Nigeria.
¹⁴ University of Port Harcourt Teaching Hospital, Rivers State, Nigeria.
¹⁵ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan.
¹⁶ Ahmadu Bello University, Zaria, Kaduna State, Nigeria.
¹⁷ College of Medicine, University of Lagos, Idi-araba, Lagos State, Nigeria.
¹⁸ R-Jolad Hospital, Gbagada, Lagos, Nigeria.
¹⁹ Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.
²⁰ Federal Medical Center, Owo, Ondo State, Nigeria.
²¹ University of Maiduguri Teaching Hospital, Maiduguri, Borno State.
²² DataTecnica LLC, Washington, DC, USA.
²³ Federal Teaching Hospital, Gombe, Gombe State, Nigeria.
²⁴ Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria.
²⁵ Delta State University, Abraka, Delta State, Nigeria.
²⁶ University of Benin, Benin City, Edo State, Nigeria.
²⁷ Lagos University Teaching Hospital, Idi-araba, Lagos State, Nigeria.
²⁸ General Hospital, Lagos Island, Lagos State, Nigeria.
²⁹ German Center for Neurodegenerative Diseases, DZNE, Tübingen, Germany.
³⁰ University of Abuja Teaching Hospital, Gwagwalada, Federal Capital Territory, Nigeria.
³¹ Department of Neurological Sciences, Rush University Medical Center, Chicago, USA.
³² Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria.
³³ University of Chicago Medicine, Department of Neurology, Chicago, USA.
³⁴ Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria.
³⁵ National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³⁶ Mid-Atlantic Permanente Medical Group, Department of Neurology, Largo, MD, USA.
³⁷ Kaiser Permanente, MidAtlantic Permanente Research Institute, Washington, DC, USA.
³⁸ University of Alabama at Birmingham, Department of Neurology, Birmingham, USA.
³⁹ Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.
⁴⁰ Department of Neurology, LSU Health Shreveport, LSU Health Shreveport Center for Brain Health, Shreveport, USA.
⁴¹ University of Florida Norman Fixel Institute for Neurological Diseases, Neurology Movement Disorders, Gainesville, USA.
⁴² The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴³ Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria.
⁴⁴ Medical University of South Carolina, Charleston, SC, USA.
⁴⁵ Michael J. Fox Foundation for Parkinson's Research, Department of Clinical Research, New York, USA.
⁴⁶ Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria.
⁴⁷ Washington University in St. Louis, St. Louis, MO, USA.
⁴⁸ Federal University of Health Sciences Teaching Hospital, Azare, Bauchi State, Nigeria.
⁴⁹ University Hospital in Cleveland Medical Center/Case Western Reserve University (UH).
⁵⁰ Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services.
⁵¹ University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
⁵² University of Maryland, Baltimore, MD, USA.
⁵³ Ochsner Clinic Foundation, New Orleans, LA, USA.
⁵⁴ Henry M. Jackson Foundation for the Advancement of Military Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵⁵ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
⁵⁶ University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria.
⁵⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
⁵⁸ UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK.
⁵⁹ National Hospital for Neurology and Neurosurgery, London, UK.
⁶⁰ Department of Neurology, Royal Free Hospital, London, UK.
⁶¹ University of Ilorin, Ilorin, Kwara State, Nigeria.
⁶² Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
⁶³ Department of Biomedical Sciences, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁶⁴ General Hospital, Isolo, Lagos State, Nigeria.
⁶⁵ Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana, Santiago 7610658, Chile.
⁶⁶ Institute of Neurogenetics and Department of Neurology, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.
⁶⁷ Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.
⁶⁸ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁶⁹ Parkinson's Foundation, NewYork, NY 10018, USA.
⁷⁰ University of Pennsylvania, Philadelphia, PA.
⁷¹ University of Cincinnati, Cincinnati, Ohio.
⁷² Emory University, Atlanta, GA.
⁷³ Morehouse College, Atlanta, GA.
⁷⁴ University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA.

PMID: 39867380
PMCID: PMC11759243
DOI: 10.1101/2025.01.14.25320205

Update in

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.
Akçimen F, Paquette K, Wild Crea P, Step K, Waldo E, Koretsky MJ, Saffie-Awad P, Achoru C, Taiwo F, Ozomma S, Onwuegbuzie G, Khani M, Grant S, Owolabi L, Okereke C, Oshinaike O, Iwuozo E, Can Akerman S, Lee PS, Oyakhire S, Osemwegie N, Daida K, Abubakar S, Olusanya A, Isayan M, Alvarez C, Traurig R, Ogunmodede A, Samuel S, Makarious MB, Sa'ad F, Olanigan R, Levine K, Ogbimi EM, Vitale D, Odiase F, Ojini F, Odeniyi O, Fang ZH, Obianozie N, Hall DA, Nwazor E, Xie T, Nwaokorie F, Padmanaban M, Nwani P, Shamim EA, Nnama A, Standaert D, Komolafe M, Dean M, Osaigbovo G, Disbrow E, Ishola I, Rawls A, Imarhiagbe F, Chandra S, Erameh C, Hinson V, Louie N, Idowu A, Solle J, Norris SA, Ibrahim A, Kilbane C, Sukumar G, Shulman LM, Ezuduemoih D, Staisch J, Breaux S, Dalgard C, Foster ER, Bello A, Ameri A, Real R, Ikwenu E, Morris HR, Anyanwu R, Furr Stimming E, Billingsley K, Alaofin W, Alvarez Jerez P, Agabi O, Hernandez DG, Akinyemi R, Arepalli S, Malik L, Owolabi R, Nyandaiti Y, Leonard HL, Wahab K, Abiodun O, Hernandez CF, Abdulai F, Iwaki H, Bardien S, Klein C, Hardy J, Houlden H, Galvelis KG, Nalls MA, Dahodwala N, Aamodt W, Hill E, Espay A, Factor S, Branson C, Blauwendraat C, Singleton… See abstract for full author list ➔ Akçimen F, et al. Brain. 2025 Oct 8:awaf379. doi: 10.1093/brain/awaf379. Online ahead of print. Brain. 2025. PMID: 41058593

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. 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. 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.

Keywords: African admixed ancestry; African ancestry; Black and African American population; Parkinson’s disease; clinical trials; disease-causing mutations; genetics; monogenic; rare variants.

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Conflict of interest statement

Competing interests KL, DV, HLL, HI, MJK and MAN declare that they are consultants employed by DataTecnica LLC, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company. MAN also owns stock from Neuron23 Inc and Character Biosciences.

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References

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This is a preprint.

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

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

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