Impact of Y chromosome loss on the risk of Parkinson's disease and progression
Loss of Y chromosome (LOY), an age-related somatic mutation, is associated with various age-related diseases, but its role in the onset and progression of Parkinson's disease (PD) remains unclear. This study investigated the relationship between blood LOY levels and the risk of PD onset and progression.
We estimated the LOY level for each male participant based on genome-wide arrays or whole genome sequencing data. We performed Cox proportional hazards regression analysis among 222,598 male participants in the UK Biobank and linear mixed model analysis involving 2574 male individuals with PD across 14 cohorts, encompassing 19,562 visits. In the Parkinson's Progression Markers Initiative (PPMI) cohort, we further compared brain structure using T1-weighted magnetic resonance imaging (MRI) scans, and carried out brain network functional connectivity analysis based on resting-state functional MRI (rs-fMRI) datasets. Additionally, we assessed the LOY status in single-nucleus RNA sequencing (snRNA-seq) data, which included 1,303,531 cells from 279 post-mortem samples across five brain regions, and performed temporal dynamic gene expression analysis.
Male participants with LOY had a slightly higher risk of developing PD during follow-up (HR = 1·16, 95% CI = 1·01-1·34, P = 0·04). Among males affected by PD, LOY carriers experienced accelerated neurodegenerative progression, manifesting as more rapid motor impairment (P = 0·0072) and cognitive decline (P = 0·0005) compared to non-LOY carriers. Patients with PD carrying LOY also exhibited decreased network functional connectivity in certain brain regions. Notably, LOY cells were particularly enriched in microglia/immune and vascular/epithelial cells, and a subset of genes in LOY-Mic P2RY12 cells were associated with PD progression.
This data-driven study highlights the potential association of LOY with the onset and progression of PD through the analysis of multi-scale data, including clinical phenotypes, brain neuroimaging maps, and molecular profiles from single-nucleus transcriptome across multi-brain regions. These findings suggest that LOY may be an accomplice to the onset and progression of PD.
G.L.'s work is supported by the Shenzhen Fundamental Research Program (JCYJ20240813151132042), National Natural Science Foundation of China (32270701, 32470708), Young Talent Recruitment Project of Guangdong (2019QN01Y139), the Science and Technology Planning Project of Guangdong Province (2023B1212060018) and Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases (ZDSYS20220606100803007). This study is supported by High-performance Computing Public Platform (Shenzhen Campus) of Sun Yat-sen University. C.R.S.'s work is supported by NIH grants NINDS/NIA R01NS115144, the U.S. Department of Defense, and the American Parkinson Disease Association Center for Advanced Parkinson Research. C.R.S.'s research work was funded in part by Aligning Science Across Parkinson's 000301 through the Michael J. Fox Foundation for Parkinson's Research (MJFF). The study was made possible in part by a philanthropic support for Illumina MEGA chip genotyping (to Brigham & Women's Hospital and C.R.S.). CHWG received funding support from an RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1; MR/W029235/1) and from the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a CC BY public copyright licence to all Author Accepted Manuscripts arising from this submission.
LOY; Onset; Parkinson's disease; Progression.
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
Declaration of interests Jean-Christophe Corvol has served in advisory boards for Alzprotect, Bayer, Biogen, Denali, Ferrer, Idorsia, iRegene, Prevail Therapeutic, Servier, Theranexus, UCB; received consulting fees from Iregene, Alzprotect, Ferrer, Biogen, Servier, and UCB; received support for attending meetings from International Movement Disorders Society; and received grants from ICM, Agence Nationale pour la Recherche (ANR), Sanofi and the Michael J Fox Foundation (unrelated to this work). Meghan C. Campbell has received grants or contracts from NIH, MJFox Foundation, WashU Department of Radiology, WashU McDonnell Foundation, Parkinson Foundation, and American Parkinson Disease Association; and received payment or honoraria for lectures from Parkinson Foundation Honoraria (unrelated to this work). Alexis Elbaz has received grants or contracts from Michael J Fox foundation, French Ministry of Agriculture, ANR (French national funding agency for research), and France Parkinson outside of this work; received payment or honoraria for lectures from Prada foundation; and participated on a Data Safety Monitoring Board or Advisory Board of ANSM (French drug agency) (unrelated to this work). Michael A. Schwarzschild has received grants or contracts from NIH, Michael J Fox Foundation, Farmer Family Foundation, Sergey Brin Family Foundation, American Parkinson's Disease Association, Cure Parkinson's, Parkinson's Foundation, Harvard School of Public Health (NIH, DoD), GE Healthcare, NINDS, The Carol T. Barrett Fund for Parkinson's Disease Research, Jane & Alan Batkin, The ABY Fund, Parkinson's Foundation, Sanofi US Services Inc., Food and Drug Administration, UCB, Novartis, Rita and Norton Reamer, Biogen, Cerevel, Cure Parkinson's, Roche, LikeMinds, Inc., Parkinson Canada, Parkinson's UK; and received consulting fees from Parkinson Study Group (PSG), Sutter Health (NIA), Northwestern Univ (NINDS), Cure Parkinson's (unrelated to this work). Pille Taba has received support for attending meetings and/or travel from the University of Tartu, Estonia (research grant); and served in Estonian Agency of Medicines, Marketing authorisation committee for medicinal products outside of this work. Sulev Kõks has received grants or contracts from European Commission, ERA-chair 668,989, MSWA grant Genomic Medicine, and The Michael J Fox Foundation; received support for attending meetings and/or travel from Perron Institute; and received other financial or non-financial interests from Founder and CEO of Prion OÜ and Founder of Genomic Therapeutics Pty Ltd (unrelated to this work). Joel S. Perlmutter has received consulting fees from CHDI—Head of Scientific Advisory Committee re:Huntington Disease Research; received payment or honoraria for lectures from St Lukes Hospital; received payment for expert testimony from Parkinson disease tremor and Treatment of someone with Parkinson disease and quadriparesis; received support for attending meetings and/or travel from Dystonia Medical Research Foundation; served as readership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Temporary Head of Huntington Study Group, Member of Executive Committee and Head of Scientific Advisory Committee of the Parkinson Study Group, and Director of the Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation (unrelated to this work). Baijayanta Maiti has received Payment or honoraria for manuscript writing from American Academy of Neurology (unrelated to this work). Roger A. Barker has received grants or contracts from MRC, EU, Cure Parkinson's, NIHR, ASAP/MJFF and Rosetrees; received Consulting fees from Novo Nordisk, UCB, BlueRock, Rinri; and served as Co-Editor in chief work for Journal of Neurology (unrelated to this work). Caroline H Williams-Gray has received grants or contracts from Cure Parkinson's, Parkinson's UK, and Rosetrees Trust; received consulting fees from Mission Therapeutics and Evidera; and participated on a Data Safety Monitoring Board or Advisory Board in Trial Steering Committee, Exenatide PD3 trial, Parkinson's UK College of Experts, and Editorial Board, Movement Disorders (unrelated to this work). The remaining authors report no competing interests. No specific funding was received for the establishment or coordination of the IGPP Consortium itself.
