[en] Heterozygous GBA1 variants increase Parkinson's disease (PD) risk with variable penetrance. We investigated the interaction between genome-wide polygenic risk scores (PRS) and severity of pathogenic GBA1 variants (GBA1PVs) to assess their combined impact on PD risk. GBA1 variants were identified from whole exome sequencing in the UK Biobank and targeted PacBio sequencing in the Luxembourg Parkinson's Study, with PRS calculated using genome-wide significant SNPs. GBA1PVs were present in 8.8% of PD patients in the UK Biobank and 9.9% in LuxPark, with carriers showing consistently higher PD risk across all PRS categories. In the highest PRS category, PD risk increased 2.3-fold in the UK Biobank and 1.6-fold in LuxPark. Severe and mild GBA1 variants conferred nearly double the risk of PD compared to risk variants. Our findings demonstrate the impact of PRS on GBA1PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1-associated PD.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) LIH - Luxembourg Institute of Health
Disciplines :
Neurology Genetics & genetic processes
Author, co-author :
HASSANIN, Emadeldin ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
LANDOULSI, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Bioinformatics Core > Research BioCore ; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg
PACHCHEK, Sinthuja ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER
NCER-PD Consortium
Krawitz, Peter; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
Maj, Carlo; Centre for Human Genetics, University of Marburg, Marburg, Germany
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Luxembourg Institute of Health > Transversal Translational Medicine ; Centre Hospitalier de Luxembourg > Department of Neurology
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
External co-authors :
yes
Language :
English
Title :
Penetrance of Parkinson's disease in GBA1 carriers depends on variant severity and polygenic background.
Publication date :
12 June 2025
Journal title :
NPJ Parkinson's Disease
eISSN :
2373-8057
Publisher :
Springer Science and Business Media LLC, United States
FNR11264123 - NCER-PD - Ncer-pd, 2015 (01/06/2015-31/05/2023) - Rejko Krüger FNR14429377 - ProtectMove II - Reduced Penetrance In Hereditary Movement Disorders: Elucidating Mechanisms Of Endogenous Disease Protection, 2020 (01/07/2020-30/06/2023) - Anne Grünewald FNR11583046 - MechEPI - Epileptogenesis Of Genetic Epilepsies, 2017 (01/04/2018-30/06/2021) - Roland Krause FNR14323864 - GenXcess - Empowering The Individuals To Access Their Personal Genome Data, 2019 (01/03/2020-28/02/2022) - Dheeraj Reddy Bobbili
Funders :
FNR - Fonds National de la Recherche
Funding text :
The FNR supported P.M. as part of the National Center of Excellence in Research on Parkinson’s disease (NCER-PD, FNR11264123) and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). The Fonds National de Recherche (FNR) supported D.R.B through the Industrial fellowship program of Luxembourg (FNR14323864).
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