Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson’s Disease in African and African Admixed Populations
Authors: Rizig Mie , Bandres-Ciga Sara , Makarious Mary B , Ojo Oluwadamilola , Crea Peter Wild , Abiodun Oladunni , Levine Kristin S , Abubakar Sani , Achoru Charles , Vitale Dan , Adeniji Olaleye , Agabi Osigwe , Koretsky Mathew J , Agulanna Uchechi , Hall Deborah A. , Akinyemi Rufus , Xie Tao , Ali Mohammed , Shamim Ejaz A. , Ani-Osheku Ifeyinwa , Padmanaban Mahesh , Arigbodi Owotemu , Standaert David G , Bello Abiodun , Dean Marissa , Erameh Cyril , Elsayed Inas , Farombi Temitope , Okunoye Olaitan , Fawale Michael , Billingsley Kimberley J , Imarhiagbe Frank , Jerez Pilar Alvarez , Iwuozo Emmanuel , Baker Breeana , Komolafe Morenikeji , Malik Laksh , Nwani Paul , Daida Kensuke , Nwazor Ernest , Miano-Burkhardt Abigail , Nyandaiti Yakub , Fang Zih-Hua , Obiabo Yahaya , Kluss Jillian H. , Odeniyi Olanike , Hernandez Dena , Odiase Francis , Tayebi Nahid , Ojini Francis , Sidranksy Ellen , Onwuegbuzie Gerald , D’Souza Andrea M. , Osaigbovo Godwin , Berhe Bahafta , Osemwegie Nosakhare , Reed Xylena , Oshinaike Olajumoke , Leonard Hampton , Otubogun Folajimi , Alvarado Chelsea X , Oyakhire Shyngle , Ozomma Simon , Samuel Sarah , Taiwo Funmilola , Wahab Kolawole , Zubair Yusuf , Iwaki Hirotaka , Kim Jonggeol Jeffrey , Morris Huw R , Hardy John , Nalls Mike , Heilbron Karl , Norcliffe-Kaufmann Lucy ,   Nigeria Parkinson 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 Cornelis , Houlden Henry , Singleton Andrew , Okubadejo Njideka 
Published: May 2023

SummaryBackgroundUnderstanding 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.MethodsHere 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.FindingsWe identified a novel common risk factor for PD and age at onset at theGBA1locus (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 identifiedGBA1associated 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.InterpretationThe present study identifies a novel African-ancestry genetic risk factor inGBA1as 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.Research in ContextEvidence Before this StudyOur 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 StudyTo 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 decreasedGBA1activity 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 EvidenceWe nominate a novel signal impactingGBA1as the major genetic risk factor for PD in the African and African admixed populations. The present study could inform futureGBA1clinical 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.