Large-scale genetic characterization of Parkinson’s disease in the African and African admixed populations
Authors: Akçimen Fulya , Paquette Kimberly , Crea Peter Wild , Saffie-Awad Paula , Achoru Charles , Taiwo Funmilola , Ozomma Simon , Onwuegbuzie Gerald , Khani Marzieh , Grant Spencer , Owolabi Lukman , Okereke Chiamaka , Oshinaike Olajumoke , Iwuozo Emmanuel , Lee Paul Suhwan , Oyakhire Shyngle , Osemwegie Nosakhare , Daida Kensuke , Abubakar Sani , Olusanya Adedunni , Isayan Mariam , Traurig Rami , Ogunmodede Adebimpe , Samuel Sarah , Makarious Mary B. , Sa’ad Fadimatu , Olanigan Rashidat , Levine Kristin , Ogbimi Ewere Marie , Vitale Dan , Odiase Francis , Koretsky Mathew J. , Ojini Francis , Odeniyi Olanike , Fang Zih-Hua , Obianozie Nkechi , Hall Deborah A. , Nwazor Ernest , Xie Tao , Nwaokorie Francisca , Padmanaban Mahesh , Nwani Paul , Shamim Ejaz A. , Nnama Alero , Standaert David , Komolafe Morenikeji , Dean Marissa , Osaigbovo Godwin , Disbrow Elizabeth , Ishola Ismaila , Rawls Ashley , Imarhiagbe Frank , Chandra Shivika , Erameh Cyril , Hinson Vanessa , Louie Naomi , Idowu Ahmed , Solle J , Norris Scott A. , Ibrahim Abdullahi , Kilbane Camilla , Sukumar Gauthaman , Shulman Lisa M. , Ezuduemoih Daniel , Staisch Julia , Breaux Sarah , Dalgard Clifton , Foster Erin R. , Bello Abiodun , Ameri Andrew , Real Raquel , Ikwenu Erica , Morris Huw R , Anyanwu Roosevelt , Stimming Erin Furr , Billingsley Kimberley , Alaofin Wemimo , Jerez Pilar Alvarez , Agabi Osigwe , Hernandez Dena G. , Akinyemi Rufus , Arepalli Sampath , Malik Laksh , Owolabi Raymond , Nyandaiti Yakub , Leonard Hampton L. , Wahab Kolawole , Step Kathryn , Abiodun Oladunni , Hernandez Carlos F. , Abdulai Fatima , Iwaki Hirotaka , Bardien Soraya , Klein Christine , Hardy John , Houlden Henry , Galvelis Kamalini Ghosh , Nalls Mike A. , Dahodwala Nabila , Aamodt Whitley , Hill Emily , Espay Alberto , Factor Stewart , Branson Chantale , Blauwendraat Cornelis , Singleton Andrew B. , Ojo Oluwadamilola , Chahine Lana M. ,   the Black and African American Connections to Parkinson’s Disease Study (BLAAC PD),   the Nigeria Parkinson’s Disease Research Network (NPDRN),   the Racial Disparities in Parkinson Disease (RaD-PD) and the Global Parkinson’s Genetics Program (GP2), Okubadejo Njideka , Bandres-Ciga Sara 
Published: January 2025

AbstractElucidating the genetic contributions to Parkinson’s disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rareGBA1coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18GBA1variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associatedGBA1variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and AsianLRRK2disease-causing mutational spectrum, includingLRRK2p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missenseLRRK2variants of uncertain significance overrepresented in cases, two of which — p.Glu268Ala and p.Arg1538Cys — had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence ofPRKNCNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.