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 BatutuKaty 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 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 Groues, Anne Grünewald, Wei Gu, Gaël Hammot, Anne Marie Hanff, Linda Hansen, Michael Heneka, Estelle Henry, Sylvia Herbrink, Sascha Herzinger, Michael 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 Mackay, Walter Maetzler, Katrin Marcus, Guilherme Marques, Patricia Martins Conde, Deborah Mcintyre, Chouaib Mediouni, Francoise Meisch, Myriam Menster, Maura Minelli, Michel Mittelbronn, Brit Mollenhauer, Friedrich Mühlschlegel, Romain Nati, Ulf Nehrbass, Sarah Nickels, Beatrice Nicolai, Jean Paul Nicolay, Fozia Noor, Marek Ostaszewski, Clarissa P. C. Gomes, Claire Pauly, Laure Pauly, Lukas Pavelka, Magali Perquin, Rosalina Ramos Lima, Armin Rauschenberger, Rajesh Rawal, Kirsten Roomp, Eduardo Rosales, Isabel Rosety, Estelle Sandt, Stefano Sapienza, Venkata Satagopam, Margaux Schmitt, Sabine Schmitz, Reinhard Schneider, Jens Schwamborn, Raquel Severino, Amir Sharify, Ekaterina Soboleva, Kate Sokolowska, Hermann Thien, Elodie Thiry, Rebecca Ting Jiin Loo, Christophe Trefois, Johanna Trouet, Olena Tsurkalenko, Michel Vaillant, Mesele Valenti, Gilles Van Cutsem, Carlos Vega, Liliana Vilas Boas, Maharshi Vyas, Richard Wade-Martins, Paul Wilmes, Evi Wollscheid-Lengeling, Gelani Zelimkhanov

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number156
Number of pages14
Journalnpj Parkinson's Disease
Volume9
Issue number1
DOIs
Publication statusPublished - 23 Nov 2023

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