@article{d1942aaa848a41218b9910fd8f142370,
title = "Penetrance of Parkinson{\textquoteright}s disease in GBA1 carriers depends on variant severity and polygenic background",
abstract = "Heterozygous GBA1 variants increase Parkinson{\textquoteright}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{\textquoteright}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.",
author = "Zied Landoulsi and Gelani Zelimkhanov and Carlos Vega and Michel Vaillant and Olena Tsurkalenko and Johanna Trouet and Hermann Thien and Maud Theresine and Kate Sokolowska and Amir Sharify and Stefano Sapienza and Olivia Roland and Ils{\'e} Richard and Lucie Remark and Armin Rauschenberger and Achilleas Pexaras and Magali Perquin and Lukas Pavelka and Laure Pauly and Claire Pauly and Fozia Noor and Sarah Nickels and Ulf Nehrbass and Maeva Munsch and Sa{\"i}da Mtimet and Michel Mittelbronn and Myriam Menster and Alexia Mendibide and Chouaib Mediouni and Deborah Mcintyre and Guilherme Marques and Marques, \{Tain{\'a} M.\} and Victoria Lorentz and Lopes, \{Ana Festas\} and Pauline Lambert and Olga Kofanova and Jochen Klucken and Sonja J{\'o}nsd{\'o}ttir and Alexander Hundt and Margaux Henry and Estelle Henry and Hanff, \{Anne Marie\} and J{\'e}r{\^o}me Graas and Marijus Giraitis and Laura Georges and Manon Gantenbein and Carlos Gamio and Jo{\"e}lle Fritz and Angelo Ferrari and \{De Bremaeker\}, Nancy and Gessica Contesotto and Ibrahim Boussaad and Guy Berchem and Sibylle B{\'e}chet and Katy Beaumont and Roxane Batutu and Myriam Alexandre and Gloria Aguayo and Geeta Acharya and Rejko Kr{\"u}ger and \{NCER-PD Consortium\}",
note = "Funding: The NCER-PD is funded by the Luxembourg National Research Fund (FNR/NCER13/BM/11264123). We would like to thank all participants of the Luxembourg Parkinson{\textquoteright}s Study for their important support to our research. Furthermore, we acknowledge the joint effort of the NCER-PD Consortium members from the partner institutions Luxembourg Center for Systems Biomedicine, Luxembourg Institute of Health, Center Hospitalier de Luxembourg, and Laboratoire National de Sant{\'e} generally contributing to the Luxembourg Parkinson{\textquoteright}s Study as listed below in the Author Information section. Parts of the computational analysis were done on the High-Performance Computing cluster of the University of Luxembourg (https://hpc.uni.lu/). The FNR supported P.M. as part of the National Center of Excellence in Research on Parkinson{\textquoteright}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). Publisher Copyright: {\textcopyright} The Author(s) 2025.",
year = "2025",
month = jun,
day = "12",
doi = "10.1038/s41531-025-00997-y",
language = "English",
volume = "11",
journal = "npj Parkinson's Disease",
issn = "2373-8057",
publisher = "Springer Nature",
number = "1",
}