Penetrance of Parkinson’s disease in GBA1 carriers depends on variant severity and polygenic background
Emadeldin Hassanin, Zied Landoulsi, Sinthuja Pachchek, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Muhammad Ali, Wim Ammerlann, Giuseppe Arena, Michele Bassis, Roxane Batutu, Katy Beaumont, Sibylle Béchet, Guy Berchem, Alexandre Bisdorff, Ibrahim Boussaad, David Bouvier, Lorieza Castillo, Gessica Contesotto, Nancy De Bremaeker, Brian Dewitt, Nico Diederich, Rene Dondelinger, Nancy E. Ramia, Angelo Ferrari, Katrin Frauenknecht, Joëlle Fritz, Carlos Gamio, Manon Gantenbein, Piotr Gawron, Laura Georges, Soumyabrata Ghosh, Marijus Giraitis, Enrico Glaab, Martine Goergen, Elisa Gómez De Lope, Jérôme Graas, Mariella Graziano, Valentin Groues, Anne Grünewald, Gaël Hammot, Anne-Marie Hanff, Linda Hansen, Michael Heneka, Estelle Henry, Margaux Henry, Sylvia Herbrink, Sascha Herzinger, Alexander Hundt, Nadine Jacoby, Sonja Jónsdóttir, Jochen Klucken, Olga Kofanova, Pauline Lambert, Zied Landoulsi, Roseline Lentz, Laura Longhino, Ana Festas Lopes, Victoria Lorentz, Tainá M. Marques, Guilherme Marques, Patricia Martins Conde, Deborah Mcintyre, Chouaib Mediouni, Francoise Meisch, Alexia Mendibide, Myriam Menster, Maura Minelli, Michel Mittelbronn, Saïda Mtimet, Maeva Munsch, Romain Nati, Ulf Nehrbass, Sarah Nickels, Beatrice Nicolai, Jean-Paul Nicolay, Fozia Noor, Clarissa P. C. Gomes, Claire Pauly, Laure Pauly, Lukas Pavelka, Magali Perquin, Achilleas Pexaras, Armin Rauschenberger, Rajesh Rawal, Lucie Remark, Ilsé Richard, Olivia Roland, Kirsten Roomp, Eduardo Rosales, Stefano Sapienza, Venkata Satagopam, Sabine Schmitz, Reinhard Schneider, Jens Schwamborn, Raquel Severino, Amir Sharify, Ruxandra Soare, Ekaterina Soboleva, Kate Sokolowska
Abstract
Abstract 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 ( GBA1 PVs ) 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. GBA1 PVs 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 GBA1 PVs penetrance, highlighting implications for genetic counseling and clinical trial design in GBA1 -associated PD.