Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.
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Akçimen Fulya, Paquette Kimberly, Wild Crea Peter, Step Kathryn, Waldo Emily, Koretsky Mathew J, Saffie-Awad Paula, Achoru Charles, Taiwo Funmilola, Ozomma Simon, Onwuegbuzie Gerald, Khani Marzieh, Grant Spencer, Owolabi Lukman, Okereke Chiamaka, Oshinaike Olajumoke, Iwuozo Emmanuel, Akerman Suleyman Can, Lee Paul Suhwan, Oyakhire Shyngle, Osemwegie Nosakhare, Daida Kensuke, Abubakar Sani, Olusanya Adedunni, Isayan Mariam, Alvarez Christiane, Traurig Rami, Ogunmodede Adebimpe, Samuel Sarah, Makarious Mary B, Sa'ad Fadimatu, Olanigan Rashidat, Levine Kristin, Ogbimi Ewere Marie, Vitale Dan, Odiase Francis, Ojini Francis, Odeniyi Olanike, Fang Zih-Hua, Obianozie Nkechi, Hall Deborah A, Nwazor Ernest, Xie Tao, Nwaokorie Francesca, 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, Furr Stimming Erin, Billingsley Kimberley, Alaofin Wemimo, Alvarez Jerez Pilar, Agabi Osigwe, Hernandez Dena G, Akinyemi Rufus, Arepalli Sampath, Malik Laksh, Owolabi Raymond, Nyandaiti Yakub, Leonard Hampton L, Wahab Kolawole, 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, Okubadejo Njideka, Bandres-Ciga Sara
Аннотация
Elucidating the genetic contributions to Parkinson's disease aetiology 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 in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among patients with Parkinson's disease, with a frequency of 4% in our case cohort. Of the 18 GBA1 variants identified, 10 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-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met and p.Glu365Lys, were not identified among the screened Parkinson's disease cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in Parkinson's disease aetiology among West African ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance, with two (p.Glu268Ala and p.Arg1538Cys) displaying higher frequencies in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs 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 Parkinson's disease in these populations. Short tandem repeat analysis also identified ATXN3 CAG repeat expansions within the pathogenic range (CAGn > 45) in three patients with Parkinson's disease of African ancestry. Novel genetic variation among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalogue of both known and novel coding and splicing variants potentially linked to Parkinson's disease aetiology in an underserved population and further conducted global and local ancestry analyses to further explore population-specific effects. 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 Parkinson's disease treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.