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Lookup NU author(s): Dr Rufus Akinyemi, Professor Camille CarrollORCiD
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© 2023 Elsevier LtdBackground: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. Methods: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. Findings: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37–1·80], p=2·397 × 10−14) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=–2·00 [SE=0·57], p=0·0005, for African ancestry; and β=–4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. Interpretation: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. Funding: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.
Author(s): Rizig M, Bandres-Ciga S, Makarious MB, Ojo OO, Crea PW, Abiodun OV, Levine KS, Abubakar SA, Achoru CO, Vitale D, Adeniji OA, Agabi OP, Koretsky MJ, Agulanna U, Hall DA, Akinyemi RO, Xie T, Ali MW, Shamim EA, Ani-Osheku I, Padmanaban M, Arigbodi OM, Standaert DG, Bello AH, Dean MN, Erameh CO, Elsayed I, Farombi TH, Okunoye O, Fawale MB, Billingsley KJ, Imarhiagbe FA, Jerez PA, Iwuozo EU, Baker B, Komolafe MA, Malik L, Nwani PO, Daida K, Nwazor EO, Miano-Burkhardt A, Nyandaiti YW, Fang Z-H, Obiabo YO, Kluss JH, Odeniyi OA, Hernandez DG, Odiase FE, Tayebi N, Ojini FI, Sidranksy E, Onwuegbuzie GA, D'Souza AM, Osaigbovo GO, Berhe B, Osemwegie N, Reed X, Oshinaike OO, Leonard HL, Otubogun FM, Alvarado CX, Oyakhire SI, Ozomma SI, Samuel SC, Taiwo FT, Wahab KW, Zubair YA, Iwaki H, Kim JJ, Morris HR, Hardy J, Heilbron K, Norcliffe-Kaufmann L, Okubadejo N, Ojo O, Abiodun O, Achoru C, Agabi O, Akinyemi R, Ali M, Arigbodi O, Bello A, Erameh C, Farombi T, Fawale M, Imarhiagbe F, Iwuozo E, Komolafe M, Nwani P, Nwazor E, Nyandaiti Y, Obiabo Y, Odeniyi O, Odiase F, Ojini F, Onwuegbuzie G, Osaigbovo G, Oshinaike O, Otubogun F, Oyakhire S, Ozomma S, Samuel S, Taiwo F, Wahab K, Zubair Y, Gams Massi D, Gueumekane Bila lamou E, Njamnshi Nfor L, Magnerou MA, Fogang Fogoum Y, Shalash A, El-FawaI H, Khedr E, Fawi G, A Eltantawi M, Salama M, El-Jaafary S, Hamed S, Tafesse Mengesha A, Alemayehu Ayele B, Melka Oda D, Zenebe Zewde Y, Debebe Gelan Y, AkpaIu A, Charway-Felli A, Stephen Sarfo F, Adjei P, Obese V, Bocoum A, Koita A, Oumar Guinto C, Coulibaly T, Maiga Y, Kone Z, Bell A, Adebowale AA, Akpekpe J, lyagba A, Wulgo AM, Arabambi B, Agu C, Dike F, Ishola I, Abiodun K, Ekenze O, Agabi Osigwe P, Balarabe S, Abubakar S, Williams U, Fall M, Mamadou Diop A, Hilaire Dominique ET, Mochan A, Modi G, Dindayal S, Ali Awadelkareem E, Dahawi M, Awadelkareem MA, Misbah S, Mushengez B, Kimambo H, Msango L, Adebayo P, OKeng K, Diekker M, URassa S, Gouider R, Ben Djebara M, Gargouri A, Kacem I, Nasri A, Mrabet S, Sghaier I, Mkada I, Atadzhanov M, Chishimba L, Jama F, Houlden H, Singleton A, Nalls M, Shamim E, Jonas C, Williamson J, Hall DA, Rosenbaum M, Davis S, Dean M, Cromer C, Smith J, Ruffrage L, Richardson J, Sipma R, Padmanaban M, Warren N, Mercado T, Disbrow E, Chauppeta B, Thomas-Dean F, Toms J, Lofton K, Rawls A, Rizer K, Black N, Solle J, O'Grady A, Sherer T, Fiske B, Blauwendraat C, Okubadejo NU, Basak AN, Tan AH, Noyce A, Akpalu A, Espay A, Martinez-Carrasco A, Medina A, Zimprich A, Brice A, Karimova A, Hernandez A, Illarionova A, Quattrone A, Singleton AB, Sobering AK, Vinuela A, Sanyaolu A, Schumacher-Schuh AF, Kishore A, Ahmad-Annuar A, Al Mubarak B, Tang B, Pizarro Galleguillos B, Jeon B, Siddiqi B, Casey B, Mollenhauer B, Carroll C, Rieder C, Pantazis CB, Comart C, Lin C-H, Klein C, Bale C, Shepherd CE, Wegel C, Martinez-Ramirez D, Hall D, Hernandez D, KP D, Nguyen D, Fon EA, Dadiotis E, Riley E, Iakovenko E, Stafford E, Gatto EM, Valente EM, Vollstedt E-J, Faghri F, Genc G, Xiromerisiou G, Hadjigorgiou G, Hiu-Fai Chan G, Arboleda G, Kaishibayeva G, Hoglinger G, Leonard H, Madoev H, Chen H, Wu H-C, Shang H, F Mata I, Keller Sarmiento IJ, Dagklis I, Tarnanas I, Aasly JO, Hoenicka J, Corvol J-C, Foo JN, Guo J, Junker J, Carr J, Kim JJ, Orozco J, Jankovic J, Shulman J, Hunter J, Solle JC, Murphy K, Nuytemans K, Kieburtz K, Lohmann K, Marek K, Mok KY, Kumar K, Levine K, Chahine LM, Lange LM, Pihlstrom L, Screven L, Stefanis L, Shulman L, Marsili L, Parnetti L, Kuhl M, Funayama M, Sharma M, Tan M, Kauffman M, Miranda M, Bustamante ML, Stamelou M, Perinan Tocino MT, Cornejo-Olivas M, Jimenez del Rio M, Koretsky M, Rodriguez-Violante M, Ellis M, Avenali M, Renteria ME, Inca-Martines MZ, Nalls MA, Nalls MA, Ibrahim Norlinah M, Umair M, Ip N, Louie N, Cheung NY-F, Mencacci NE, Wood N, Williams N, Hattori N, Abdul Murad NA, Ibrahim NM, Monchi O, Oztop Cakmak O, Oztop Cakmak POC, Lewis PA, Pastor P, Reyes-Perez P, Saffie Awad P, Chana P, Chan P, Kung P-J, Chan P, Pal P, Lingappa Kukkle P, Ojha R, Kaiyrzhanov R, Kruger R, Amouri R, Weil R, Rajan R, Alcalay R, Wu R-M, Borgohain R, Sassi SB, Khachatryan S, El-Sadig S, Wu S, Groppa S, Azmin S, Lim S-Y, Ur-Rehman S, Ertan S, Stott S, Jasaitye S, Chowdhury S, Dumanis S, Bardien S, Lubbe S, Koks S, Dey S, Foroud T, Fon T, Beach T, Gasser T, Anderson T, Nguyen T, Schirinzi T, Shiraishi T, Pitcher T, Tumas V, Mohamed W, Kamel WA, Luo W, Zhou X, Zewde YZ, Song Y, Wen Y, Wu Y, Joong Kim Y, Tavadyan Z
Publication type: Article
Publication status: Published
Journal: The Lancet Neurology
Year: 2023
Volume: 22
Issue: 11
Pages: 1015-1025
Print publication date: 01/11/2023
Online publication date: 23/08/2023
Acceptance date: 02/04/2023
ISSN (print): 1474-4422
ISSN (electronic): 1474-4465
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/S1474-4422(23)00283-1
DOI: 10.1016/S1474-4422(23)00283-1
PubMed id: 37633302
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