Analysis of rare Parkinson’s disease variants in millions of people
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Published:2024-01-08
Issue:1
Volume:10
Page:
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ISSN:2373-8057
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Container-title:npj Parkinson's Disease
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language:en
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Short-container-title:npj Parkinsons Dis.
Author:
Pitz VanessaORCID, Makarious Mary B.ORCID, Bandres-Ciga Sara, Iwaki Hirotaka, Aslibekyan Stella, Auton Adam, Babalola Elizabeth, Bell Robert K., Bielenberg Jessica, Bryc Katarzyna, Bullis Emily, Coker Daniella, Partida Gabriel Cuellar, Dhamija Devika, Das Sayantan, Elson Sarah L., Eriksson Nicholas, Filshtein Teresa, Fitch Alison, Fletez-Brant Kipper, Fontanillas Pierre, Freyman Will, Granka Julie M., Hernandez Alejandro, Hicks Barry, Hinds David A., Jewett Ethan M., Jiang Yunxuan, Kukar Katelyn, Kwong Alan, Lin Keng-Han, Llamas Bianca A., Lowe Maya, McCreight Jey C., McIntyre Matthew H., Micheletti Steven J., Moreno Meghan E., Nandakumar Priyanka, Nguyen Dominique T., Noblin Elizabeth S., O’Connell Jared, Petrakovitz Aaron A., Poznik G. David, Reynoso Alexandra, Schumacher Morgan, Shastri Anjali J., Shelton Janie F., Shi Jingchunzi, Shringarpure Suyash, Su Qiaojuan Jane, Tat Susana A., Tchakouté Christophe Toukam, Tran Vinh, Tung Joyce Y., Wang Xin, Wang Wei, Weldon Catherine H., Wilton Peter, Wong Corinna D., Singleton Andrew B.ORCID, Nalls MikeORCID, Heilbron Karl, Blauwendraat CornelisORCID,
Abstract
AbstractAlthough many rare variants have been reportedly associated with Parkinson’s disease (PD), many have not been replicated or have failed to replicate. Here, we conduct a large-scale replication of rare PD variants. We assessed a total of 27,590 PD cases, 6701 PD proxies, and 3,106,080 controls from three data sets: 23andMe, Inc., UK Biobank, and AMP-PD. Based on well-known PD genes, 834 variants of interest were selected from the ClinVar annotated 23andMe dataset. We performed a meta-analysis using summary statistics of all three studies. The meta-analysis resulted in five significant variants after Bonferroni correction, including variants in GBA1 and LRRK2. Another eight variants are strong candidate variants for their association with PD. Here, we provide the largest rare variant meta-analysis to date, providing information on confirmed and newly identified variants for their association with PD using several large databases. Additionally we also show the complexities of studying rare variants in large-scale cohorts.
Funder
U.S. Department of Health & Human Services | NIH | National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Neurology
Reference56 articles.
1. Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020). 2. Bandres-Ciga, S., Diez-Fairen, M., Kim, J. J. & Singleton, A. B. Genetics of Parkinson’s disease: an introspection of its journey towards precision medicine. Neurobiol. Dis. 137, 104782 (2020). 3. Papadimitriou, A. et al. Mutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance? Neurology 52, 651–654 (1999). 4. Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004). 5. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
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