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Abstract
Summary 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.
MethodsWe 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.
FindingsWe 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
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.
FundingThe 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.
Details
1 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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 UCL Movement Disorders Centre, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
4 College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria
5 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; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
6 General Hospital, Isolo, Lagos State, Nigeria
7 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; Data Tecnica International, Washington, DC, USA
8 Ahmadu Bello University, Zaria, Kaduna State, Nigeria
9 Jos University Teaching Hospital, Jos, Plateau State, Nigeria
10 Data Tecnica International, Washington, DC, USA
11 Federal Medical Centre, Abeokuta, Ogun State, Nigeria
12 Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria
13 Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
14 Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
15 Department of Neurology, University of Chicago Medicine, Chicago, IL, USA
16 Federal Teaching Hospital Gombe, Gombe State, Nigeria
17 Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Kaiser Permanente Mid-Atlantic States, Largo, MD, USA; MidAtlantic Permanente Research Institute, Rockville, MD, USA
18 Asokoro District Hospital, Asokoro, Abuja, Nigeria
19 Delta State University, Abraka, Delta State, Nigeria
20 Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA
21 University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria
22 Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria
23 Faculty of Pharmacy, University of Gezira, Wadmadani, Sudan
24 University College Hospital, Ibadan, Oyo State, Nigeria
25 Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
26 University of Benin, Benin City, Edo State, Nigeria
27 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; 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
28 Benue State University, Makurdi, Benue State, Nigeria
29 Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
30 Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria
31 University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Nigeria
32 German Center for Neurodegenerative Diseases, Tuebingen, Germany
33 Federal University of Health Sciences, Otukpo, Benue State, Nigeria
34 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
35 General Hospital, Lagos Island, Lagos State, Nigeria
36 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
37 University of Abuja, Abuja, Federal Capital Territory, Nigeria
38 University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
39 Lagos State University College of Medicine, Ikeja, Lagos State, Nigeria
40 Federal Medical Center, Ebute Metta, Lagos State, Nigeria
41 National Hospital, Abuja, Federal Capital Territory, Nigeria
42 University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria
43 University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria; University of Ilorin, Ilorin, Kwara State, Nigeria
44 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
45 23andMe, Sunnyvale, CA, USA
46 College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria; Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria