Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson’s study
Sinthuja Pachchek, Zied Landoulsi, Lukas Pavelka, Claudia Schulte, Elena Buena‐Atienza, Caspar Groß, Ann‐Kathrin Hauser, Dheeraj Reddy Bobbili, Nicolas Casadei, Patrick May, Rejko Krüger, Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Muhammad Ali, Wim Ammerlann, Giuseppe Arena, Rudi Balling, Michele Bassis, Roxane Batutu, Katy Beaumont, Regina Becker, Camille Bellora, Guy Berchem, Daniela Berg, Alexandre Bisdorff, Ibrahim Boussaad, David Bouvier, Kathrin Brockmann, Jessica Calmes, Lorieza Castillo, Gessica Contesotto, Nancy De Bremaeker, Nico J. Diederich, Rene Dondelinger, Nancy E. Ramia, Daniela Esteves, Guy Fagherazzi, Jean-Yves Ferrand, Katrin Frauenknecht, Manon Gantenbein, Thomas Gasser, Piotr Gawron, Soumyabrata Ghosh, Marijus Giraitis, Enrico Glaab, Martine Goergen, Elisa Gómez de Lope, Jérôme Graas, Mariella Graziano, Valentin Grouès, Anne Grünewald, Wei Gu, Gaël Hammot, Anne-Marie Hanff, Linda Hansen, Michael T. Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michaël Heymann, Michele Hu, Alexander Hundt, Nadine Jacoby, Jacek Jaroslaw Lebioda, Yohan Jarosz, Sonja Jónsdóttir, Quentin Klopfenstein, Jochen Klucken, Rejko Krüger, Pauline Lambert, Roseline Lentz, Inga Liepelt, Robert Liszka, Laura Longhino, Victoria Lorentz, Paula Cristina Lupu, Tainá M. Marques, Clare E. Mackay, Walter Maetzler, Katrin Marcus, Guilherme Fernandes Marques, Patricia Martins Conde, Deborah McIntyre, Chouaib Mediouni, Françoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Friedrich Mühlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Béatrice Nicolai, Jean-Paul Nicolay, Fozia Noor, Marek Ostaszewski, Clarissa P. C. Gomes, Claire Pauly
Abstract
Heterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.