TY - JOUR
T1 - Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations
T2 - a genome-wide association study
AU - Nigeria Parkinson Disease Research Network
AU - International Parkinson's Disease Genomics Consortium Africa
AU - Black and African American Connections to Parkinson's Disease Study Group
AU - 23andMe Research Team
AU - Global Parkinson's Genetics Program
AU - Rizig, Mie
AU - Bandres-Ciga, Sara
AU - Makarious, Mary B.
AU - Ojo, Oluwadamilola Omolara
AU - Crea, Peter Wild
AU - Abiodun, Oladunni Victoria
AU - Levine, Kristin S.
AU - Abubakar, Sani Atta
AU - Achoru, Charles Obiora
AU - Vitale, Dan
AU - Adeniji, Olaleye Akinmola
AU - Agabi, Osigwe Paul
AU - Koretsky, Mathew J.
AU - Agulanna, Uchechi
AU - Hall, Deborah A.
AU - Akinyemi, Rufus Olusola
AU - Xie, Tao
AU - Ali, Mohammed Wulgo
AU - Shamim, Ejaz A.
AU - Ani-Osheku, Ifeyinwa
AU - Padmanaban, Mahesh
AU - Arigbodi, Ohwotemu Michael
AU - Standaert, David G.
AU - Bello, Abiodun Hamzat
AU - Dean, Marissa N.
AU - Erameh, Cyril Oshomah
AU - Elsayed, Inas
AU - Farombi, Temitope Hannah
AU - Okunoye, Olaitan
AU - Fawale, Michael Bimbola
AU - Billingsley, Kimberley J.
AU - Imarhiagbe, Frank Aiwansoba
AU - Jerez, Pilar Alvarez
AU - Iwuozo, Emmanuel Uzodinma
AU - Baker, Breeana
AU - Komolafe, Morenikeji Adeyoyin
AU - Malik, Laksh
AU - Nwani, Paul Osemeke
AU - Daida, Kensuke
AU - Nwazor, Ernest Okwundu
AU - Miano-Burkhardt, Abigail
AU - Nyandaiti, Yakub Wilberforce
AU - Fang, Zih Hua
AU - Obiabo, Yahaya Olugbo
AU - Kluss, Jillian H.
AU - Odeniyi, Olanike Adedoyin
AU - Hernandez, Dena G.
AU - Odiase, Francis Ehidiamen
AU - Tayebi, Nahid
AU - Adebayo, Philip
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/11
Y1 - 2023/11
N2 - Background: 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.
AB - Background: 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.
UR - http://www.scopus.com/inward/record.url?scp=85174164547&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(23)00283-1
DO - 10.1016/S1474-4422(23)00283-1
M3 - Article
C2 - 37633302
AN - SCOPUS:85174164547
SN - 1474-4422
VL - 22
SP - 1015
EP - 1025
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 11
ER -