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Meta-Analysis
. 2023 Nov;22(11):1015-1025.
doi: 10.1016/S1474-4422(23)00283-1. Epub 2023 Aug 23.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

Mie Rizig  1 , Sara Bandres-Ciga  2 , Mary B Makarious  3 , Oluwadamilola Omolara Ojo  4 , Peter Wild Crea  5 , Oladunni Victoria Abiodun  6 , Kristin S Levine  7 , Sani Atta Abubakar  8 , Charles Obiora Achoru  9 , Dan Vitale  10 , Olaleye Akinmola Adeniji  11 , Osigwe Paul Agabi  4 , Mathew J Koretsky  2 , Uchechi Agulanna  12 , Deborah A Hall  13 , Rufus Olusola Akinyemi  14 , Tao Xie  15 , Mohammed Wulgo Ali  16 , Ejaz A Shamim  17 , Ifeyinwa Ani-Osheku  18 , Mahesh Padmanaban  15 , Ohwotemu Michael Arigbodi  19 , David G Standaert  20 , Abiodun Hamzat Bello  21 , Marissa N Dean  20 , Cyril Oshomah Erameh  22 , Inas Elsayed  23 , Temitope Hannah Farombi  24 , Olaitan Okunoye  1 , Michael Bimbola Fawale  25 , Kimberley J Billingsley  5 , Frank Aiwansoba Imarhiagbe  26 , Pilar Alvarez Jerez  27 , Emmanuel Uzodinma Iwuozo  28 , Breeana Baker  2 , Morenikeji Adeyoyin Komolafe  25 , Laksh Malik  2 , Paul Osemeke Nwani  29 , Kensuke Daida  5 , Ernest Okwundu Nwazor  30 , Abigail Miano-Burkhardt  5 , Yakub Wilberforce Nyandaiti  31 , Zih-Hua Fang  32 , Yahaya Olugbo Obiabo  33 , Jillian H Kluss  34 , Olanike Adedoyin Odeniyi  35 , Dena G Hernandez  34 , Francis Ehidiamen Odiase  26 , Nahid Tayebi  36 , Francis Ibe Ojini  4 , Ellen Sidranksy  36 , Gerald Awele Onwuegbuzie  37 , Andrea M D'Souza  36 , Godwin Osawaru Osaigbovo  9 , Bahafta Berhe  36 , Nosakhare Osemwegie  38 , Xylena Reed  2 , Olajumoke Olufemi Oshinaike  39 , Hampton L Leonard  7 , Folajimi Morenikeji Otubogun  40 , Chelsea X Alvarado  7 , Shyngle Imiewan Oyakhire  41 , Simon Izuchukwu Ozomma  42 , Sarah Chabiri Samuel  31 , Funmilola Tolulope Taiwo  24 , Kolawole Wasiu Wahab  43 , Yusuf Agboola Zubair  41 , Hirotaka Iwaki  7 , Jonggeol Jeffrey Kim  5 , Huw R Morris  1 , John Hardy  44 , Mike A Nalls  10 , Karl Heilbron  45 , Lucy Norcliffe-Kaufmann  45 ; Nigeria Parkinson Disease Research Network; International Parkinson's Disease Genomics Consortium Africa; Black and African American Connections to Parkinson's Disease Study Group; 23andMe Research Team; Cornelis Blauwendraat  5 , Henry Houlden  1 , Andrew Singleton  46 , Njideka Ulunma Okubadejo  47 ; Global Parkinson's Genetics Program
Collaborators, Affiliations
Meta-Analysis

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study

Mie Rizig et al. Lancet Neurol. 2023 Nov.

Abstract

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.

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Conflict of interest statement

Declaration of interests DV, HI, HLL, KSL, CXA, and MAN's participation in this project was part of a competitive contract awarded to Data Tecnica International by the US National Institutes of Health (NIH) to support open science research. MAN also currently serves on the scientific advisory board for Character Biosciences and Neuron 23. KH is employed by 23andMe and holds stock or stock options in 23andMe. AS, MBM, PAJ, CB, KD, MJK, JJK, and PWC are employed by the NIH. AS also declares funding for the present work from the Michael J Fox Foundation (MJFF) and Aligning Science Across Parkinson's (ASAP); royalties for a diagnostic for stroke (unrelated to the current work); honoraria for associate editorial work for the journals Movement Disorders and npj Parkinson's Disease; and travel support from the Chan Zuckerberg Initiative to attend annual investigators’ meeting, MJFF to attend Parkinson's Progression Marker Initiative annual meeting, and Weill Cornell to give grand rounds. The spouse of AS is an employee of GeneDx. OOk, IE, HI, JHK, and DV declare funding from the NIH (1ZIA AG000534-04). HI also declares honoraria from GP2 for a steering committee meeting and from MJFF for a data community meeting. DGS declares support for the present work from ASAP (for the BLAAC-PD study); research support from the NIH (P50 108675), the MJFF, the Parkinson Foundation of the National Capital Area, the American Parkinson Disease Association, AbbVie, and Genentech; book royalties from McGraw Hill; consulting fees from AbbVie, Curium Pharma, F Hoffman-La Roche, Appello Pharma, and Blue Rock Therapeutics; participation on a data safety monitoring board or advisory board for Sanofi-Aventis, Theravance, and Alnylam Pharmaceuticals; being Deputy Editor of the journal Movement Disorders; and being Chair of the Scientific Advisory Board of the American Parkinson Disease Association. DAH declares support for the present work from the NIH, the MJFF, the CHDI Foundation, Parkinson's Foundation, Lundbeck, Uniqure, and Neurocrine. TX declares research funding from the MJFF, the American Parkinson's Disease Association, and the NIH; and consulting fees from Parkinson's Foundation and CVS Caremark. HH and JH declare research funding by the Medical Research Council (UK), the Wellcome Trust, the MSA Trust, NIHR University College London Hospitals Biomedical Research Centre (NIHR-BRC), the MJFF, the Fidelity Trust, the Rosetrees Trust, the Guarantors of Brain, SOLVE-RD, and the Dolby Family Fund. HRM declares support from the MJFF related to this work; grants not related to this work from PSP Association, CBD Solutions, Drake Foundation, and Cure Parkinson's Trust; consulting fees from Roche, Amylyx, and Aprinoia; speaker's honoraria from Kyowa-Kirin, the British Medical Journal, and the Movement Disorders Society; travel support from the MJFF and the Movement Disorders Society; and being on the advisory board for Cure PSP Association, the Association of British Neurologists Movement Disorders special interest group, and the Association of British Neurologists Neurogenetics advisory group. HRM is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). ES declares funding for the present work from the US National Human Genome Research Institute (NHGRI) Intramural Research Program; grants from ASAP and MJFF; and a cooperative research and development agreement with Roche. EAS declares funding for the present work from the MJFF; and travel support from the MJFF. MND declares funding for the present work from MJFF; grant support from ASAP; speaker's honoraria from the Parkinson's Foundation; and is a member of the Parkinson's Foundation Gulf Coast advisory board. Z-HF declares salary support from the MJFF. OOOj declares a study grant from the NIHR; honoraria for educational courses from the International Parkinson and Movement Disorder Society (IPMDS); travel support from P2 for an annual investigators’ meeting and from the IPMDS for congress attendance; and is a member of the executive committee of the IPMDS. NUO declares a study grant from the NIHR; travel support and honoraria for educational courses from the IPMDS; and being Chair of the IPMDS Africa Section. UA declares a study grant from the NIHR. RA declares grant support from the NIH (U01HG010273, U19AG074865), the UK Royal Society and the African Academy of Sciences Future Leaders—African Independent Research (FLR/R1/191813, FCG/R1/201034), and the Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK (GBHI ALZ UK-21- 24204). TF declares speaker's honoraria from Roche; travel support from the Alzheimer's Association; and is a member of the Alzheimer's Disease International medical and scientific advisory panel. CB declares support from ASAP. KD declares a Japan Society for the Promotion of Science Research Fellowship. JJK declares participation in the graduate school programme for Queen Mary University London (London, UK). PAJ declares participation in the graduate school programme for University College London (London, UK). MBM declares participation in a summer internship at Genentech/Roche (unrelated to the current work). All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Study design
Figure created with BioRender.com. eQTL=expression quantitative trait locus. GWAS=genome-wide association study.
Figure 2:
Figure 2:. African and African admixed GWAS meta-analysis assessing Parkinson’s disease risk
Manhattan plot showing the significance of the association as −log10.(p value) against chromosomes at a genomic scale (Bonferroni correction highlighted in grey at 5 × 10 3). GWAS=genome-wide association study.
Figure 3:
Figure 3:. Miami plot comparing European versus African and African admixed GWAS meta-analyses of Parkinson’s disease risk
Randomly sampled 1200 cases and 2445 controls were included in each of the GWAS meta-analyses. The grey horizontal lines indicate the significance threshold of 5 × 10 3. GWAS=genome-wide association study.
Figure 4
Figure 4. LocusZoom plot displaying African and African admixed Parkinson’s disease GWAS meta-analysis summary statistics versus African American eQTL summary statistics from blood
eQTL=expression quantitative trait locus. GWAS=genome-wide association study.
See this image and copyright information in PMC

Update of

  • Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.
    Rizig M, Bandres-Ciga S, Makarious MB, Ojo O, Crea PW, Abiodun O, Levine KS, Abubakar S, Achoru C, Vitale D, Adeniji O, Agabi O, Koretsky MJ, Agulanna U, Hall DA, Akinyemi R, Xie T, Ali M, Shamim EA, Ani-Osheku I, Padmanaban M, Arigbodi O, Standaert DG, Bello A, Dean M, Erameh C, Elsayed I, Farombi T, Okunoye O, Fawale M, Billingsley KJ, Imarhiagbe F, Jerez PA, Iwuozo E, Baker B, Komolafe M, Malik L, Nwani P, Daida K, Nwazor E, Miano-Burkhardt A, Nyandaiti Y, Fang ZH, Obiabo Y, Kluss JH, Odeniyi O, Hernandez D, Odiase F, Tayebi N, Ojini F, Sidranksy E, Onwuegbuzie G, D'Souza AM, Osaigbovo G, Berhe B, Osemwegie N, Reed X, Oshinaike O, Leonard H, Otubogun F, Alvarado CX, Oyakhire S, Ozomma S, Samuel S, Taiwo F, Wahab K, Zubair Y, Iwaki H, Kim JJ, Morris HR, Hardy J, Nalls M, Heilbron K, Norcliffe-Kaufmann L; Disease Research Network, International Parkinson’s Disease Genomics Consortium - Africa (IPDGC Africa), Black and African American Connections to Parkinson’s Disease (BLAAC PD) Study Group, the 23andMe Research Team; Blauwendraat C, Houlden H, Singleton A, Okubadejo N. Rizig M, et al. medRxiv [Preprint]. 2023 May 7:2023.05.05.23289529. doi: 10.1101/2023.05.05.23289529. medRxiv. 2023. Update in: Lancet Neurol. 2023 Nov;22(11):1015-1025. doi: 10.1016/S1474-4422(23)00283-1. PMID: 37398408 Free PMC article. Updated. Preprint.

Comment in

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