Abstract

Although 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.

Details

Title
Analysis of rare Parkinson’s disease variants in millions of people
Author
Pitz, Vanessa 1   VIAFID ORCID Logo  ; Makarious, Mary B. 2   VIAFID ORCID Logo  ; Bandres-Ciga, Sara 3 ; Iwaki, Hirotaka 4 ; Aslibekyan, Stella 5 ; Auton, Adam 5 ; Babalola, Elizabeth 5 ; Bell, Robert K. 5 ; Bielenberg, Jessica 5 ; Bryc, Katarzyna 5 ; Bullis, Emily 5 ; Coker, Daniella 5 ; Partida, Gabriel Cuellar 5 ; Dhamija, Devika 5 ; Das, Sayantan 5 ; Elson, Sarah L. 5 ; Eriksson, Nicholas 5 ; Filshtein, Teresa 5 ; Fitch, Alison 5 ; Fletez-Brant, Kipper 5 ; Fontanillas, Pierre 5 ; Freyman, Will 5 ; Granka, Julie M. 5 ; Hernandez, Alejandro 5 ; Hicks, Barry 5 ; Hinds, David A. 5 ; Jewett, Ethan M. 5 ; Jiang, Yunxuan 5 ; Kukar, Katelyn 5 ; Kwong, Alan 5 ; Lin, Keng-Han 5 ; Llamas, Bianca A. 5 ; Lowe, Maya 5 ; McCreight, Jey C. 5 ; McIntyre, Matthew H. 5 ; Micheletti, Steven J. 5 ; Moreno, Meghan E. 5 ; Nandakumar, Priyanka 5 ; Nguyen, Dominique T. 5 ; Noblin, Elizabeth S. 5 ; O’Connell, Jared 5 ; Petrakovitz, Aaron A. 5 ; Poznik, G. David 5 ; Reynoso, Alexandra 5 ; Schumacher, Morgan 5 ; Shastri, Anjali J. 5 ; Shelton, Janie F. 5 ; Shi, Jingchunzi 5 ; Shringarpure, Suyash 5 ; Su, Qiaojuan Jane 5 ; Tat, Susana A. 5 ; Tchakouté, Christophe Toukam 5 ; Tran, Vinh 5 ; Tung, Joyce Y. 5 ; Wang, Xin 5 ; Wang, Wei 5 ; Weldon, Catherine H. 5 ; Wilton, Peter 5 ; Wong, Corinna D. 5 ; Singleton, Andrew B. 6   VIAFID ORCID Logo  ; Nalls, Mike 4   VIAFID ORCID Logo  ; Heilbron, Karl 5 ; Blauwendraat, Cornelis 7   VIAFID ORCID Logo 

1  National Institutes of Health, Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
2  National Institutes of Health, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences, London, UK (GRID:grid.436283.8) (ISNI:0000 0004 0612 2631); University College London, UCL Movement Disorders Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201) 
3  National Institutes of Health, Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
4  National Institutes of Health, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); National Institutes of Health, Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); Data Tecnica International, Washington, DC, USA (GRID:grid.511118.d) 
5  23andMe, Inc., Sunnyvale, USA (GRID:grid.420283.f) (ISNI:0000 0004 0626 0858) 
6  National Institutes of Health, Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); National Institutes of Health, Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
7  National Institutes of Health, Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); National Institutes of Health, Center for Alzheimer’s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
Pages
11
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
23738057
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41531-023-00608-8
ProQuest document ID
2911664339
Copyright
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.