Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.
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Rizig Mie, Bandres-Ciga Sara, Makarious Mary B, Ojo Oluwadamilola Omolara, Crea Peter Wild, Abiodun Oladunni Victoria, Levine Kristin S, Abubakar Sani Atta, Achoru Charles Obiora, Vitale Dan, Adeniji Olaleye Akinmola, Agabi Osigwe Paul, Koretsky Mathew J, Agulanna Uchechi, Hall Deborah A, Akinyemi Rufus Olusola, Xie Tao, Ali Mohammed Wulgo, Shamim Ejaz A, Ani-Osheku Ifeyinwa, Padmanaban Mahesh, Arigbodi Ohwotemu Michael, Standaert David G, Bello Abiodun Hamzat, Dean Marissa N, Erameh Cyril Oshomah, Elsayed Inas, Farombi Temitope Hannah, Okunoye Olaitan, Fawale Michael Bimbola, Billingsley Kimberley J, Imarhiagbe Frank Aiwansoba, Jerez Pilar Alvarez, Iwuozo Emmanuel Uzodinma, Baker Breeana, Komolafe Morenikeji Adeyoyin, Malik Laksh, Nwani Paul Osemeke, Daida Kensuke, Nwazor Ernest Okwundu, Miano-Burkhardt Abigail, Nyandaiti Yakub Wilberforce, Fang Zih-Hua, Obiabo Yahaya Olugbo, Kluss Jillian H, Odeniyi Olanike Adedoyin, Hernandez Dena G, Odiase Francis Ehidiamen, Tayebi Nahid, Ojini Francis Ibe, Sidranksy Ellen, Onwuegbuzie Gerald Awele, D'Souza Andrea M, Osaigbovo Godwin Osawaru, Berhe Bahafta, Osemwegie Nosakhare, Reed Xylena, Oshinaike Olajumoke Olufemi, Leonard Hampton L, Otubogun Folajimi Morenikeji, Alvarado Chelsea X, Oyakhire Shyngle Imiewan, Ozomma Simon Izuchukwu, Samuel Sarah Chabiri, Taiwo Funmilola Tolulope, Wahab Kolawole Wasiu, Zubair Yusuf Agboola, Iwaki Hirotaka, Kim Jonggeol Jeffrey, Morris Huw R, Hardy John, Nalls Mike A, Heilbron Karl, Norcliffe-Kaufmann Lucy, 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, Blauwendraat Cornelis, Houlden Henry, Singleton Andrew, Okubadejo Njideka Ulunma, Global Parkinson's Genetics Program
Аннотация
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.