Analysis of rare Parkinson's disease variants in millions of people

Vanessa Pitz; Mary B Makarious; Sara Bandres-Ciga; Hirotaka Iwaki; 23andMe Research Team; Andrew B Singleton; Mike Nalls; Karl Heilbron; Cornelis Blauwendraat

doi:10.1038/s41531-023-00608-8

Analysis of rare Parkinson's disease variants in millions of people

NPJ Parkinsons Dis. 2024 Jan 8;10(1):11. doi: 10.1038/s41531-023-00608-8.

Authors

Vanessa Pitz¹, Mary B Makarious^{2

3

4}, Sara Bandres-Ciga⁵, Hirotaka Iwaki^{2

5

6}; 23andMe Research Team; Andrew B Singleton^{2

5}, Mike Nalls^{2

5

6}, Karl Heilbron^#⁷, Cornelis Blauwendraat^#^{8

5}

Collaborators

23andMe Research Team:
Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K Bell, Jessica Bielenberg, Katarzyna Bryc, Emily Bullis, Daniella Coker, Gabriel Cuellar Partida, Devika Dhamija, Sayantan Das, Sarah L Elson, Nicholas Eriksson, Teresa Filshtein, Alison Fitch, Kipper Fletez-Brant, Pierre Fontanillas, Will Freyman, Julie M Granka, Alejandro Hernandez, Barry Hicks, David A Hinds, Ethan M Jewett, Yunxuan Jiang, Katelyn Kukar, Alan Kwong, Keng-Han Lin, Bianca A Llamas, Maya Lowe, Jey C McCreight, Matthew H McIntyre, Steven J Micheletti, Meghan E Moreno, Priyanka Nandakumar, Dominique T Nguyen, Elizabeth S Noblin, Jared O'Connell, Aaron A Petrakovitz, G David Poznik, Alexandra Reynoso, Morgan Schumacher, Anjali J Shastri, Janie F Shelton, Jingchunzi Shi, Suyash Shringarpure, Qiaojuan Jane Su, Susana A Tat, Christophe Toukam Tchakouté, Vinh Tran, Joyce Y Tung, Xin Wang, Wei Wang, Catherine H Weldon, Peter Wilton, Corinna D Wong

Affiliations

¹ Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. vanessa.pitz@nih.gov.
² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
⁴ UCL Movement Disorders Centre, University College London, London, UK.
⁵ Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁶ Data Tecnica International, Washington, DC, USA.
⁷ 23andMe, Inc., Sunnyvale, CA, USA.
⁸ Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

^# Contributed equally.

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.

Abstract

Grants and funding