Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.
Autor: | Rizig M; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; UCL Movement Disorders Centre, University College London, London, WC1N 3BG, UK., Bandres-Ciga S; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Makarious MB; UCL Movement Disorders Centre, University College London, London, WC1N 3BG, UK.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Ojo O; College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria., Crea PW; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Abiodun O; General Hospital, Isolo, Lagos State, Nigeria., Levine KS; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Data Tecnica International, Washington, DC, USA., Abubakar S; Ahmadu Bello University, Zaria, Kaduna State, Nigeria., Achoru C; Jos University Teaching Hospital, Jos, Plateau State, Nigeria., Vitale D; Data Tecnica International, Washington, DC, USA., Adeniji O; Federal Medical Centre, Abeokuta, Ogun State, Nigeria., Agabi O; College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria., Koretsky MJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Agulanna U; Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria., Hall DA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA., Akinyemi R; Neuroscience and Ageing Research Unit, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria., Xie T; Department of Neurology, University of Chicago Medicine, Chicago, Illinois, USA., Ali M; Federal Teaching Hospital Gombe, Gombe State, Nigeria., Shamim EA; Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.; Kaiser Permanente Mid-Atlantic States, Largo, Maryland, USA.; MidAtlantic Permanente Research Institute, Rockville, Maryland, USA., Ani-Osheku I; Asokoro District Hospital, Asokoro, Abuja, Nigeria., Padmanaban M; Department of Neurology, University of Chicago Medicine, Chicago, Illinois, USA., Arigbodi O; Delta State University, Abraka, Delta State, Nigeria., Standaert DG; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA., Bello A; University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria., Dean M; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA., Erameh C; Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria., Elsayed I; Faculty of Pharmacy, University of Gezira, Wadmadani, 20, Sudan., Farombi T; University College Hospital, Ibadan, Oyo State, Nigeria., Okunoye O; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Fawale M; Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria., Billingsley KJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Imarhiagbe F; University of Benin, Benin City, Edo State, Nigeria., Jerez PA; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Iwuozo E; Benue State University, Makurdi, Benue State, Nigeria., Baker B; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Komolafe M; Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria., Malik L; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Nwani P; Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria., Daida K; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Nwazor E; Rivers State University Teaching Hospital, Port Harcourt, Rivers State, Nigeria., Miano-Burkhardt A; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Nyandaiti Y; University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Nigeria., Fang ZH; German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany., Obiabo Y; Federal University of Health Sciences, Otukpo, Benue State, Nigeria., Kluss JH; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Odeniyi O; General Hospital, Lagos Island, Lagos State, Nigeria., Hernandez D; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Odiase F; University of Benin, Benin City, Edo State, Nigeria., Tayebi N; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Ojini F; College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria., Sidranksy E; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Onwuegbuzie G; University of Abuja, Abuja, Federal Capital Territory, Nigeria., D'Souza AM; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Osaigbovo G; Jos University Teaching Hospital, Jos, Plateau State, Nigeria., Berhe B; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA., Osemwegie N; University of Port Harcourt, Port Harcourt, Rivers State, Nigeria., Reed X; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814., Oshinaike O; Lagos State University College of Medicine, Ikeja, Lagos State, Nigeria., Leonard H; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Data Tecnica International, Washington, DC, USA., Otubogun F; Federal Medical Center, Ebute Metta, Lagos State, Nigeria., Alvarado CX; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Data Tecnica International, Washington, DC, USA., Oyakhire S; National Hospital, Abuja, Federal Capital Territory, Nigeria., Ozomma S; University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria., Samuel S; University of Maiduguri Teaching Hospital, Maiduguri, Borno State, Nigeria., Taiwo F; University College Hospital, Ibadan, Oyo State, Nigeria., Wahab K; University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria.; University of Ilorin, Ilorin, Kwara State, Nigeria., Zubair Y; National Hospital, Abuja, Federal Capital Territory, Nigeria., Iwaki H; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Data Tecnica International, Washington, DC, USA., Kim JJ; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Morris HR; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; UCL Movement Disorders Centre, University College London, London, WC1N 3BG, UK., Hardy J; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Nalls M; Data Tecnica International, Washington, DC, USA., Heilbron K; 23andMe, Inc., Sunnyvale, CA, USA., Norcliffe-Kaufmann L; 23andMe, Inc., Sunnyvale, CA, USA., Blauwendraat C; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Singleton A; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA, 20814.; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Okubadejo N; College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria. |
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Jazyk: | angličtina |
Zdroj: | MedRxiv : the preprint server for health sciences [medRxiv] 2023 May 07. Date of Electronic Publication: 2023 May 07. |
DOI: | 10.1101/2023.05.05.23289529 |
Abstrakt: | Background: Understanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. The African and African admixed populations enable mapping of complex traits given their greater levels of genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. Methods: Here we perform a comprehensive genome-wide assessment of Parkinson's disease (PD) in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. Findings: We identified a novel common risk factor for PD and age at onset at the GBA1 locus (risk, rs3115534-G; OR=1.58, 95% CI = 1.37 - 1.80, P=2.397E-14; age at onset, BETA =-2.004, SE =0.57, P = 0.0005), that was found to be rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk variants are coding mutations, here we suggest a novel functional mechanism consistent with a trend in decreasing glucocerebrosidase activity levels. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant may not cause Gaucher disease. Additionally, the prevalence of Gaucher's disease in Africa is low. Interpretation: The present study identifies a novel African-ancestry genetic risk factor in GBA1 as a major mechanistic basis of PD in the African and African admixed populations. This striking result contrasts to previous work in Northern European populations, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a particularly crucial point as the field moves toward precision medicine in PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups in such trials. Given the distinctive genetics of these underrepresented populations, their inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology. This opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk. Evidence Before This Study: Our current understanding of Parkinson's disease (PD) is disproportionately based on studying populations of European ancestry, leading to a significant gap in our knowledge about the genetics, clinical characteristics, and pathophysiology in underrepresented populations. This is particularly notable in individuals of African and African admixed ancestries. Over the last two decades, we have witnessed a revolution in the research area of complex genetic diseases. In the PD field, large-scale genome-wide association studies in the European, Asian, and Latin American populations have identified multiple risk loci associated with disease. These include 78 loci and 90 independent signals associated with PD risk in the European population, nine replicated loci and two novel population-specific signals in the Asian population, and a total of 11 novel loci recently nominated through multi-ancestry GWAS efforts.Nevertheless, the African and African admixed populations remain completely unexplored in the context of PD genetics. Added Value of This Study: To address the lack of diversity in our research field, this study aimed to conduct the first genome-wide assessment of PD genetics in the African and African admixed populations. Here, we identified a genetic risk factor linked to PD etiology, dissected African-specific differences in risk and age at onset, characterized known genetic risk factors, and highlighted the utility of the African and African admixed risk haplotype substructure for future fine-mapping efforts. We identified a novel disease mechanism via expression changes consistent with decreased GBA1 activity levels. Future large scale single cell expression studies should investigate the neuronal populations in which expression differences are most prominent. This novel mechanism may hold promise for future efficient RNA-based therapeutic strategies such as antisense oligonucleotides or short interfering RNAs aimed at preventing and decreasing disease risk. We envisage that these data generated under the umbrella of the Global Parkinson's Genetics Program (GP2) will shed light on the molecular mechanisms involved in the disease process and might pave the way for future clinical trials and therapeutic interventions. This work represents a valuable resource in an underserved population, supporting pioneering research within GP2 and beyond. Deciphering causal and genetic risk factors in all these ancestries will help determine whether interventions, potential targets for disease modifying treatment, and prevention strategies that are being studied in the European populations are relevant to the African and African admixed populations. Implications of All the Available Evidence: We nominate a novel signal impacting GBA1 as the major genetic risk factor for PD in the African and African admixed populations. The present study could inform future GBA1 clinical trials, improving patient stratification. In this regard, genetic testing can help to design trials likely to provide meaningful and actionable answers. It is our hope that these findings may ultimately have clinical utility for this underrepresented population. |
Databáze: | MEDLINE |
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